Multimedia Systems (2019) 25:109–118

https://doi.org/10.1007/s00530-017-0580-7

SPECIAL ISSUE PAPER

Segmentation of blood vessels using rule-based and machine-

learning-based methods: a review
Fengjun Zhao1 · Yanrong Chen1 · Yuqing Hou1 · Xiaowei He1

Published online: 13 December 2017

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Abstract
Vessel segmentation as a component of medical image processing is the prerequisite for accurate diagnosis of vascular-related
diseases. Manual delineation of blood vessels has been turned out to be time consuming and observer dependent. Therefore,
much effort has been dedicated to the automatic or semi-automatic vessel segmentation methods. Previous literatures have
reviewed the state of vessel segmentation methods from various perspectives. However, their reviews did not take the mod-
ern machine-learning methods especially deep neural networks into account. In this paper, we reviewed the state-of-the-art
vessel segmentation methods by dividing them into two categories, rule-based, and machine-learning-based methods. The
rule-based methods discriminate vessel structure from background relying on intuitively and exquisitely designed rule sets,
while the machine-learning-based methods carry out the segmentation by self-learned rules from the previous experience.
Instead of exhaustively listing all vessel segmentation methods, this paper focuses on the well-known blood vessel segmen-
tation methods in recent years, to give readers a glimpse of the current state and future direction of segmentation technique
for blood vessels.

Keywords  Blood vessel · Segmentation · Rule-based · Machine learning · Deep neural network

1 Introduction growing number of automatic and semi-automatic (or inter-

The primary role of blood vessels in vertebrates is to sup-
ply oxygen and nutrients to the surrounding cells and takes
metabolic wastes away [1]. Vascular malfunctions can result
in many vascular-related diseases such as cardiac–cerebral
vascular diseases, peripheral vascular diseases, and retinal
vascular disorders. Therefore, early diagnosis and precaution
of vascular-related diseases can greatly reduce the mortal-
ity and disability. Vessel segmentation, as a component of
medical image processing, is the prerequisite of accurate
diagnosis of vascular-related diseases. Manual delineation
by experts has been considered as golden standard, but it
is time consuming and observer dependent. Therefore, a
Electronic supplementary material  The online version of this
article (https://doi.org/10.1007/s00530-017-0580-7) contains
supplementary material, which is available to authorized users.
* Xiaowei He
hexw@nwu.edu.cn
1
School of Information Sciences and Technology, Northwest
University, Xi’an 710069, Shaanxi, China
active) vessel segmentation methods have been developed
for the diagnosis of vascular-related diseases.
Several groups have reviewed the state of vessel segmen-
tation methods from various perspectives. To the best of our
knowledge, Kirbas and Quek [2] reviewed vessel extraction
techniques for the first time based on different mathematic
categories. Then, Lesage et al. [3] surveyed three-dimen-
sional (3D) vessel lumen segmentation techniques from the
viewpoints of models, features, and extraction schemes.
These two literatures are important references for new prac-
titioners just beginning with vessel segmentation. After-
wards, Bibiloni et al. [4] surveyed the segmentation of curvi-
linear objects, including blood vessels as well as other thin,
long, line-like structures. Loizou [5] summarized the carotid
artery image and video segmentation in ultrasound imag-
ing, which focused on the determination of intima–media
thickness (IMT). The above literatures mainly reviewed
the methods based on presumed rules, which are designed
intuitively and exquisitely by experts. In other words, these
segmentation methods are devised using the experience of
human beings rather than machines.

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In addition, Fraz et al. [6] fully analyzed and catego-
rized the blood vessel segmentation methodologies on reti-
nal images. They mainly focused on the methods based on
machine learning. The procedure of vessel segmentation is
carried out by self-learned rules from the previous samples.
These segmentation methods can be approximately divided
into supervised and unsupervised methods. In the first cat-
egory, they systematically investigated vessel segmenta-
tion with artificial neural networks, support vector machine
(SVM), K-nearest neighbor, and Gaussian mixture model. In
the second category, they introduced the application of fuzzy
C-means, Bayesian approaches, etc. However, the state-of-
the-art machine-learning methods have not yet been involved
in vessel segmentation by then. Recently, large amount of
novel supervised or unsupervised vessel segmentation meth-
ods have been proposed, among which the deep learning-
based methods gain enormous success in the latest 5 years
[7]. Hence, it is of great importance to incorporate these up-
to-date methods into the community of vessel segmentation.
In this paper, we classify the state-of-the-art vessel seg-
mentation methods into two major categories, rule-based
methods, and machine-learning-based methods. The rule-
based methods discriminate vessel structure from back-
ground relying on the intuitively and exquisitely designed
rule sets, while the machine-learning-based methods carry
out the segmentation by self-learned rules from the previous
experience. Then, we further subdivide each category into
subclasses mainly based on the literatures from Web of Sci-
ence in recent years (Fig. S1 in Supplementary materials).
Instead of exhaustively listing all the vessel segmentation
methods, this paper focuses on the well-known methods in
recent years.
2 Rule‑based method
In this category, numerous classification strategies have been
proposed. Their principle of classification varies, such as
mathematic categories, the procedure of vessel extraction,
and the degree of manual interaction. Nowadays, the most
commonly used classifications are based on rules consisting
of all the above principles. In a similar way of [8], we subdi-
vide the most cited rule-based methods into Hessian matrix,
marching filtering, mathematical morphology, minimal path,
active contour, and graph-based methods (Fig. S1 in Sup-
plementary materials).
2.1 Hessian matrix method
Blood vessels are generally thin, elongating, and bright
compared with the surrounding background. Sato et al. and
Frangi et al. [9, 10] enhanced the image of blood vessels
using multi-scale vesselness method, in which the value of
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F. Zhao et al.
each pixel represents its affinity with vascular region. The
eigenvalue of a Hessian matrix can be exploited to form a
discriminant function, which has maximum responses for
structures like blood vessels. Similarly, Krissian et al. [11]
utilized Hessian matrix method to obtain vessel centerlines,
and then reconstructed vessel walls with the information of
vascular diameters. Zhou et al. [12] enhanced the coronary
artery by 3D multi-scale filtering and Hessian matrices, and
then tracked each coronary artery and identified the branches
using 3D rolling balloon region growing.
The Hessian matrix method has two drawbacks. First,
a Gaussian function is usually used to eliminate the influ-
ence of noise on vesselness calculation. It applies the same
scale on both blood vessels and background, leading to dis-
turbance from adjacent structure. Hence, Xiao et al. [13]
replaced the Gaussian function by bi-Gaussian filtering,
which allows independent selection of scale in blood ves-
sels and in background. Second, the Hessian matrix method
is sensitive to gradient. Therefore, the sharp boundaries
between objective and background will affect the seg-
mentation of blood vessels. To handle this problem, Zhao
et al. [14] patched these sharp boundaries from the region
of interest using a smooth operation according to the sur-
rounding background voxels. This strategy finely remedies
the false-positive response of Hessian matrix methods on
sharp boundaries, but at the expense of increased computa-
tion time.
2.2 Marching filtering method
Marching filtering method assumes that the intensity along
the cross section of a blood vessel has Gaussian-like profile.
Ricci and Perfetti invented the line detector as a marching
filter for the segmentation of retinal blood vessels [15]. Line
detector evaluates the average intensity along lines of fixed
length through the target pixel from different orientations.
Moreover, Nguyen et al. [16] combined the line detector
with multi-scale techniques by altering the length of a basic
line detector. The final segmentation is attained through
the linear combination of line responses at various scales.
The marching filters with line detectors take original blood
vessel images as inputs, but sometimes fail on images with
high micro-vessel density and background noise. Thus,
Ding et al. [17] presented an integrated filter for 3D vessel
segmentation. Their method incorporates the advantages of
multi-scale line detectors and Hessian matrix filters, which
performs well in the segmentation of micro-vessels.
Hessian matrix and line detector approaches have a com-
mon limitation. They make an implicit assumption that only
single tubular structures are locally presented, which pre-
cludes the application on complex blood vessels [9, 10, 16].
Qian et al. [18] proposed a segmentation method to relax
the assumption of single tubular structures. They captured
Segmentation of blood vessels using rule-based and machine-learning-based methods: a review 111
common properties shared by polar neighborhood intensity
profiles in all types of vascular points. The method improves
the performance on vascular bifurcations based on the neigh-
borhood intensity profile in spherical polar coordinates.
However, it is sensitive to structural noise in proximity to
background structures. Therefore, Rivest-Henault et al. [19]
defined a 3D curvilinear structure detection filter based on
structure-ball (SBall) analysis. The SBall is constructed by
evaluating second-order numerical differences in various
directions. Since it is not specific to any specific distribution
or profile of blood vessels, it can depict crossing structures
and junctions.
Except for using single feature in spatial domain, the
marching filter can also be designed in multiple ways. Zhang
et al. [20] employed a pair of filters, the zero-mean Gaussian
filter, and the first-order derivative of Gaussian, to detect
blood vessels. Lajevardi et al. [21] extracted blood vessels
using a family of matched filters in frequency domain, where
the templates for blood vessels are defined as formal spatial
graphs derived from the retinal vascular network. Moreover,
Kovacs et al. [22] proposed a novel marching template based
on generalized Gabor function. They reconstructed the con-
tours of blood vessels using the extracted centerlines and the
prior knowledge acquired from training database.
2.3 Mathematical morphology method
Traditional mathematical morphology methods utilize struc-
ture elements (SEs) for medical image analysis, which rely
on basic operations, such as erosion, dilation, opening, and
closing [23]. These mathematical morphology operations
are often used as a pre-processing in the extraction of tubu-
lar structures [24]. Subsequently, more complex morphol-
ogy methods have been developed, including watersheds,
gray-level hit-or-miss transform, and connective filter, which
have been involved in 3D vessel filtering and segmentation
[25–27].
Recently, Babin et al. extended the morphological pro-
file by introducing more complex ring-shaped SEs [28], and
further defined the novel orientation-based line-shaped SEs
[29]. Hereon, the line-shaped SEs incorporate the idea of
multi-scale approach into a multi-orientation morphology
method, improving the computational efficiency of vessel
segmentation. Moreover, Dufour et al. [30] performed a spa-
tial variant morphological closing operation on 3D cerebral
vascular images based on the corrected directional field.
The initial directional field calculated via Hessian matrix is
refined using mathematical thinning and dilating operation,
guided by the thresholded metrics of Hessian matrix. Most
recently, Sigurosson et al. [31] combined directional math-
ematical morphology with fuzzy classification. After feature
extraction through advanced morphological directional filter
based on the contrast of vessels and their linear connectivity,
pixel classification was performed according to the fusion of
these resulting features.
An apparent advantage of complex mathematical mor-
phological methods over the basic ones lies in their capacity
of self-adaptive direction and scale recognition, benefited
from the exquisite design of SEs. Nevertheless, the above
complex morphological methods generally fail on microvas-
culature when conducting direction estimation. Therefore,
there should be further investigation on accurate direction
estimation of multi-scale blood vessels.
2.4 Minimal path method
Minimal path techniques are commonly employed in inter-
active frameworks. The method captures the global optimal
curve of a contour-dependent energy formulation between
user-supplied start and endpoints [32]. Minimal path meth-
ods have the superiority of global minimization, high com-
putational efficiency, and simple incorporation of user infor-
mation. Wang et al. [33] proposed a vessel segmentation
method that requires only a few mouse clicks. The method
seeks an optimal path between given seed points by mini-
mizing a cost function. Li and Yezzi [34] invented a four
dimensional (4D) minimal path method for vessel extraction.
They modeled each blood vessel as a 4D curves, consisting
of three spatial coordinates and an extra vascular diameter
dimension. In addition, Zhu et al. [44] segmented 3D coro-
nary arteries by minimizing the average edge cost along the
path in discrete 4D graph. It can simultaneously extract the
centerline and radius on the cross section of the coronary
artery without any image pre-processing. The limitation of
these minimal path methods is that they do not consider ves-
sel orientation during vessel tracking.
Therefore, Mohan et al. [35] associated the 4D path to
anisotropic potentials, which exploited the orientation of
blood vessels. Afterwards, Benmansaour and Cohen [36]
incorporated the information of vascular orientations by an
anisotropic metric based on the optimally oriented flux. The
metric is well-oriented along the direction of blood vessels,
allowing higher velocity on the vascular centerline and pro-
viding a good estimate of the vessel radius. Cetin et al. [37]
viewed the vessel segmentation problem from the perspec-
tive of tensor estimation and tractography as in diffusion
tensor imaging. The model can capture the whole vessel
trees through automatic branch detection algorithms with
single seed point.
The minimal path method performs well on the blood
vessel confined by the user-supplied seed points, which
has been widely used in vessel segmentation especially
for large vessels, such as aorta and carotid artery. How-
ever, the extraction of complex vascular networks like
coronary arterial networks and cerebral blood vessels is
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still troublesome, since the user-supplied seeds can hardly
cover the entire networks.
2.5 Active contour method
Based on different energy formulation (implicit or
explicit), active contour methods can be broadly divided
into two subclasses: level set method and snake-based
method. Developed by Chan and Vese [38], level set
method converts the minimal partition problem into the
implicit energy minimization. The method has gained
much attention in both natural and medical image seg-
mentation [39, 40]. For example, Lorigo et  al. [41]
modeled the vessel boundary as a manifold that evolves
iteratively to minimize an energy criterion. Manniesing
et al. [42] improved the level set segmentation of vascular
structures with image enhancement methods by combin-
ing a smooth vessel filter based on a geometrical analysis
of the Hessian eigenvalue. However, these level set-based
methods lead to unwanted leakage to background regions
because of the absence of constraints during function evo-
lution. Therefore, Manniesing et al. [43] later presented
an 3D vessel tracking approach, which guided the evolu-
tion of the surface by analyzing its skeleton topology and
imposing shape constraints. Forkert et al. [44] integrated
an additional vesselness force in the level set formulation.
This method weights the internal energy lower if the gra-
dient direction of the level set is similar to the direction
of the vesselness eigenvector.
Depending on explicit Lagrangian contour evolutional
formulations, snake has become one of the most active
research areas in medical image segmentation [45]. Xu
et al. [46] applied snake model to detect the boundary
of intima–media for IMT measurement, in which two
contours are initialized from line segments generated by
Hough transform, and then, dual snake model is evolved
simultaneously to detect boundary. Moreover, Yuanzhi
et al. [47] elaborately designed a segmentation method for
thin blood vessels with low contrast through the introduc-
tion of a constrained B-snake. This method starts with the
extraction of vessel axis from the original CT angiogram,
followed by the shape- and size-constrained snake-based
vessel boundary delineation on cross sections.
The active contour method can be implemented either
automatically or interactively for vessel segmentation. In
general, this method performs worse on the segmentation
of blood vessels than on the segmentation of regional
organs, such as livers and lungs. This is because this
method is sensitive to the initialization, which results in
the poor accuracy for the thin and elongated structure of
blood vessels.
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F. Zhao et al.
2.6 Graph‑based method
Graph-based methods, especially graph cuts, transfer the prob-
lem of global optimal segmentation into energy minimization
[48]. These methods have been applied to multi-organ segmen-
tation from CT imaging [49]. However, the graph cut method
generally fails to extract blood vessels, since the energy mini-
mization tends to shrink for curvilinear structures. To handle
this problem, the graph-based method needs prior knowledge
or the collaboration with other pre-processing techniques [50].
Bauer et al. [51] separated multiple blood vessel trees
effectively using shape priors and graph cut method. First,
tree structures are formed in a top–down fashion, which uses
knowledge about the blood direction in tubular networks
based on centerline extraction. Second, these tree structures
are incorporated as a shape prior for constrained graph cut
segmentation. Esneault et al. [52] combined the graph cut
method with a geometrical moment-based detector of cylin-
drical shapes within the min-cut/max-flow energy minimiza-
tion framework. This method automates the segmentation
by adding a data term into the widely used Boykov’s graph
cuts algorithm.
On the other hand, Zhao et al. [53] segmented the retinal
vasculature in three steps: image inhomogeneity correction,
vessel enhancement, and graph-based contour segmentation.
The first two steps as pre-processing enhance the image of
retinal blood vessels and facilitate the subsequent segmen-
tation. Hernandez-Vela et al. [54] combined vesselness,
geodesic paths, and a multi-scale edgeness map with graph
cuts approach, which proceeded vessel segmentation by
global optimization of the graph cuts energy function. Roy-
chowdhury et al. [55] presented a graph-based method that
exploited a new adaptive cylinder flux (ACF)-based connec-
tivity framework, which was formulated based on random
walks. With the help of ACF-based connectivity framework,
the global optimal segmentation can be achieved without any
prior knowledge.
Couple with prior knowledge and pre-processing, graph-
based method has been successfully adopted to the area of
vessel segmentation. This method models the segmentation
of vessel from background as finding the best cut across a
graph, which is solved by optimization. However, the graph-
based method is vulnerable to pre-processing, image quality,
and even optimization parameters. Thus, suitable denois-
ing, pre-processing, and even parameter tuning are required
before the utilization of graph-based method.
3 Machine‑learning‑based method
Machine-learning-based method puts vessel segmentation as
the problem of pixel classification by assigning each pixel as
vessel or non-vessel. Pixel classification generally consists
Segmentation of blood vessels using rule-based and machine-learning-based methods: a review 113
of training and testing. In the training stage, the method
learns the correct classification of pixels from known labels
(ground truth), and then, in test stage, the trained classifier is
examined on previously unseen pixels. This machine-learn-
ing-based method is the typical supervised method, while
some other machine-learning methods are unsupervised,
such as K-means clustering, which learns the features for
classification themselves without given labels in the training
stage. Thus, both the supervised and unsupervised vessel
segmentation methods are categorized as machine-learning-
based methods. We further divide machine-learning-based
methods into the conventional machine-learning, decision-
tree-based method, and deep neural networks (Fig. S1 in
Supplementary materials).
3.1 Conventional machine learning
The basic function of artificial neural networks (NNs) is to
learn, remember, and then generalize the data to produce
new information [56]. Gardner et al. [57] applied a back
propagation multilayer NNs to retinal vascular tree segmen-
tation. For efficient computation, Sinthanayothin et al. [58]
used a multilayer perceptron NNs for vessel detection. Each
pixel is classified using the first principal component after
principal components analysis (PCA), combining with the
edge strength values from the patch centered on the current
pixel. Recently, Diego et al. [8] suggested the feed-forward
multilayer NNs based on a 7D vector, consisting of gray-
level and moment-invariant features. Although NNs have
gained much attention in various fields, they are seldom used
in the segmentation of blood vessels. In fact, accurate weight
calculation for NNs requires large amount of training data,
which exceeds the computational capability of most personal
computers before the popularization of parallel computing.
K-nearest neighbor can also be used to delineate blood
vessels in advantage of its simplicity [59]. For example,
Staal et al. [60] presented a ridge-based vessel segmenta-
tion method with a K-nearest neighbor classifier in retinal
images. Moreover, Gaussian mixture model is another con-
ventional machine-learning-based method used for vessel
segmentation. It assumes that the histograms of blood ves-
sels and its surrounding backgrounds comply with multiple
Gaussian distributions [61]. Recently, Roychowdhury et al.
[62] suggested a three-stage blood vessel segmentation algo-
rithm using fundus photograph. They first pre-processed the
green plane of a fundus image to extract major vessels, then
classified all the remaining pixels using a Gaussian mix-
ture model classifier with a set of eight features, and finally
combined the major portions of the blood vessels with the
classified vessel pixels.
The K-means and Fuzzy C-means clustering as typical
unsupervised machine-learning methods, are used in reti-
nal vessel extraction as well. Bhuiyan et al. [63] applied
Fuzzy C-means clustering to classify retinal vessels based
on the textural feature extraction. Kande et al. [64] enhanced
the contrast of blood vessels using matching filtering, and
then segmented vascular tree from retinal images by spa-
tially weighted Fuzzy C-means clustering. Clustering meth-
ods, such as K-means, can also be used as pre-processing
to reduce the negative impact of bright lesions in fundus
images, followed by vessel extraction with rule-based meth-
ods [65].
Support vector machines (SVM) is one of the most distin-
guished machine-learning-based methods for medical image
segmentation for its well-justified theoretical basis [66].
When applied to vessel extraction, SVM has to be collabo-
rated with other feature extraction approaches, e.g., march-
ing filtering [15]. Xu et al. [67] utilized a two-step method
for retinal vessel segmentation to overcome the variations
in the contrast of large and thin vessels. They first extracted
large vessel by adaptive local thresholding, and then adopted
SVM classification and tracking growth to segment the thin
blood vessels. Afterwards, You et al. [68] designed a scheme
based on radial projection and SVM method to extract both
the large and the thin retinal blood vessels. Radial projection
is used to locate vessel centerlines from narrow vessels with
low contrast, followed by vessel enhancement through modi-
fication of a steerable complex wavelet. Then, the vessel
pixel is presented by a feature vector through line strength,
where the vector is provided for SVM training. Besides,
Agurto et al. [69] presented a multi-scale method to detect
neovascularization in the optic discs. Actually, because of
its ability of local pattern recognition, textural features have
great potential complements to intensity-based features for
vessel segmentation [70].
3.2 Decision‑tree‑based method
Built from the whole data set covering all features, decision-
tree algorithms are effective for providing human-readable
rules of classification [71]. However, they are vulnerable
to small perturbations in the learning data set [72]. It has
been demonstrated that bagging techniques can effectively
alleviate this problem [73]. As an ensemble of decision trees,
random forest combines random subspace method and bag-
ging techniques, and has become a popular technique for
classification, prediction, and variable selection [74]. Both
decision trees and random forests have been brought into the
segmentation of blood vessel.
Fraz et  al. [75] segmented retinal blood vessel from
retinal photograph using an ensemble system of bagged
and boosted decision trees. Subsequently, they applied the
boosted decision-tree method into the retinal vessel segmen-
tation in multi-ethnic school children image with a different
feature vector [76]. It is demonstrated that the ensemble-
based method provides a tool for clinical large population
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studies. Furthermore, Shahrian et al. [77] constructed a clas-
sifier based on ensembles of n decision trees to segment
vessels in color retinal images. They reduced the data dimen-
sion and increased the discriminability of the feature sets by
PCA and linear discriminant analysis (LDA), respectively.
The bagging technique is implemented to provide independ-
ent training and test image sets, which overcomes the prob-
lem of overfitting.
Aslani et al. [78] adopted a random forest vessel seg-
mentation method using 17 features for its superiority in
speed, simplicity, and information fusion. The combination
of individually strong features leads to a better discrimi-
nation between vessel and non-vessel pixels. Cherry et al.
[79] suggested a marginal artery localization method from
computed tomography colonography using sequential Monte
Carlo tracking by random forest regression. The random for-
est algorithm was employed for intelligent cue fusion and
decision making, which achieved high sensitivity and robust-
ness. Moreover, Schneider et al. [80] developed a framework
for 3D vessel segmentation and centerline extraction based
on oblique random forests and Hough voting. It relies on a
steerable filter for the efficient computation of local image
features at different scale and orientation. Until now, we find
that almost all the random forests based vessel segmentation
methods have to deal with handcrafted feature extraction,
which is labor intensive and time consuming. Therefore,
Wang et al. [81] tackled this problem using a superior clas-
sifier, i.e., the convolutional NN. Convolutional NN (that
will be descripted in Sect. 3.3), performing as a trainable
hierarchical feature extractor, can automatically learn fea-
tures from the raw images and greatly save the time spent
on handcrafted feature extraction.
3.3 Deep neural networks
With the development of computation capability, deep neu-
ral networks (NNs) have won numerous contests in image
processing and machine learning, Deep NNs allow com-
putational models composed of multiple processing layers
to learn representative knowledge of data through multiple
levels of abstraction [82]. Compared with conventional NNs,
deep neural networks can effectively and robustly train net-
works using efficient activation functions and dropout strat-
egy [83, 84]. Amongst a variety of deep NNs, the most suc-
cessful type of models for image analysis is convolutional
neural networks (CNNs). The CNNs have two advantages:
first, image features are automatically learned instead of
handcrafted feature extraction as in conventional machine
learning; second, the procedure of automatic feature extrac-
tion with multiple layers is hierarchical from simple to com-
plex. Therefore, the CNNs have drawn much attention in
numerous applications, especially in medical image analysis
[85].
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F. Zhao et al.
To the best of our knowledge, Liskowski et  al. [86]
published the first paper that genuinely applied the deep
convolutional neural network to the segmentation of reti-
nal blood vessels. They exhaustively introduced the CNNs
form the view of local connectivity, parameter sharing
and pooling, as well as the combination with the problem
of vessel segmentation. Since then, the CNNs have been
fully exploited in numerous vessel extraction applications.
Khalaf et al. [87] modified the segmentation of retinal
vessels to reduce the intra-class variance by formulating
the problem as a three-class problem that differentiates
large vessels, small vessels, and background areas. They
found that the combination of convolutional kernels with
different sizes in CNNs achieved the best sensitivity and
specificity. Wu et al. [88] trained a deep CNN to estimate
the local vessel probability via PCA and nearest neigh-
bor search, and fed the resulting map into a probabilistic
tracking framework to extract the entire connected ves-
sel trees. Similarly, Prentasic et al. [89] applied CNNs
to vessel segmentation in optical coherence tomography
angiography (OCT-A) images. With manual segmentation
as the ground truth, the results demonstrate high effective-
ness of CNNs in OCT-A images. Moreover, Maji et al. [90]
suggested an ensemble of CNNs for vessel segmentation
in fundus color images. They first trained an ensemble of
deep convolutional neural networks to segment vessel and
non-vessel areas, and then averaged the responses of the
individual CNNs.
Most recently, Li et al. [91] viewed the vessel segmen-
tation as an issue of cross-modality data transformation
from retinal image to vessel map. A wide and deep neu-
ral network with strong induction ability is required to
model the relation between the retinal image and vessel
map. This method reduces the impact of subjective fac-
tors, since it needs no pre-processing, but at the cost of
increased computation. Furthermore, Moeskops et al. [92]
investigated the transfer learning capacity of a single CNN
on different segmentation tasks. They demonstrated that
the segmentation performance of a CNN trained specifi-
cally for each task was equivalent to that of the combined
training of three tasks (brain MRI, breast MRI, and car-
diac CTA). This means that a trained CNN on the tissue
segmentation can be potentially used in coronary artery
segmentation without vessel-specific training. In addition,
Annunziata et al. [93] observed that the filters learned by
the lower layers of convolutional sparse coding (CSC)
for curvilinear structure segmentation were similar to the
handcrafted filters. Thus, they proposed an efficient ves-
sel segmentation approach by combining the CSC filters
with handcrafted filters, which achieved high speed and
discriminative power simultaneously.
Segmentation of blood vessels using rule-based and machine-learning-based methods: a review 115
4 Conclusions and discussion
In this paper, we have reviewed the most commonly used
vessel segmentation methods in recent years. The machine-
learning-based methods are usually more computational
expensive than the rule-based methods, because the training
involves large amount of data. However, the machine-learn-
ing-based methods, especially deep neural networks, take
raw medical images as input without manual feature extrac-
tion, thus dramatically improve the accuracy and robustness
of vessel segmentation. The detailed assessment of different
vessel segmentation methods can be found in Supplementary
materials. As a summary, the conclusions and trends of the
latest vessel segmentation methods are described as the fol-
lowing aspects.
4.1 Vessel segmentation is closely related
to centerline extraction
Vessel centerline extraction is equally important as vessel
segmentation for the topological analysis of vascular net-
works [94, 95]. In most case, centerline extraction is con-
ducted on binary images after vessel segmentation [96–98].
However, it is synchronized with the vessel segmentation in
some applications [99]. Among different methods, minimal
path vessel segmentation method is most likely to be accom-
panied with centerline extraction, which is manifested by the
path tracking between the given seed points in blood vessels.
4.2 Hybrid method gradually replaces the method
with single technique
Hybrid methods have been increasingly adopted to build
discriminative vessel detection method. Typical hybrid
methods are the combination within rule-based methods,
and between rule-based and machine-learning-based meth-
ods. The first type of combination is a powerful tool used
for feature extraction, but requires exquisite design and is
only suitable for a specific type of medical images [42, 52,
54]. The second type combines the advantages of fast mul-
tiple feature extraction in rule-based methods and the robust
classifier in machine-learning-based methods [31, 78, 100].
4.3 Deep learning will be fully exploited in vessel
segmentation
Vessel segmentation with deep neural networks has shown
great superiority over rule-based methods and conven-
tional neural networks. Nowadays, we find that the CNNs
come into the application of retinal vessel segmentation
and achieve huge success in two public databases, i.e., the
DRIVE and STARE databases. However, these deep learn-
ing methods are seldom involved in the segmentation of cer-
ebral blood vessel and coronary artery, likely due to the lack
of standard labeled databases. The requirement of massive
data is a characteristic of machine-learning-based methods,
and the more data we collect, the more robust classifier can
we train. Hence, the adoption of deep neural networks into
other vessel segmentation tasks heavily depends on the con-
struction of the standard database. In addition, users may
also have to participate in the labeling of database with inter-
active techniques, in which the label is subsequently checked
and modified by experts.
Acknowledgements  This work was supported in part by the National
Natural Science Foundation of China under Grant Nos. 61601363,
61372046, 61640418, 61401264, 11571012, 81530058, 61601154,
and 61502387, the National Key R&D Program of China under Grant
No. 2016YFC1300300, the Science and Technology Plan Program
in Shaanxi Province of China under Grant Nos. 2013K12-20-12 and
2015KW-002, the Natural Science Research Plan Program in Shaanxi
Province of China under Grant Nos. 2017JQ6017, 2015JM6322, and
2015JZ019, and the Scientific Research Foundation of Northwest
University.
Compliance with ethical standards 
Conflict of interest  All authors declare that they have no conflict of
interest in our research.
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