applied

sciences
Article
Analysis of Clinical Profiles, Deformities, and Plantar Pressure
Patterns in Diabetic Foot Syndrome
Claudia Giacomozzi 1, * , Giada Lullini 2 , Alberto Leardini 3 , Paolo Caravaggi 3 , Maurizio Ortolani 3 ,
Giulio Marchesini 4 , Luca Baccolini 4 and Lisa Berti 3,5

1 Department of Cardiovascular, Endocrine-Metabolic Diseases and Aging, Italian National Institute of Health,
00161 Rome, Italy
2 UOC Medicina Riabilitativa e Neuroriabilitazione, IRCCS Istituto Scienze Neurologiche, 40139 Bologna, Italy;
giada.lullini@isnb.it
3 Movement Analysis Laboratory, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy; leardini@ior.it (A.L.);
paolo.caravaggi@ior.it (P.C.); maurizio.ortolani@ior.it (M.O.); lisa.berti@ior.it (L.B.)
4 IRCCS-Azienda Ospedaliera di Bologna Policlinico Sant’Orsola-Malpighi, 40138 Bologna, Italy;
giulio.marchesini@unibo.it (G.M.); baccoliniluca@gmail.com (L.B.)
5 Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
* Correspondence: claudia.giacomozzi@iss.it

Abstract: Diabetic foot syndrome refers to heterogeneous clinical and biomechanical profiles, which
render predictive models unsatisfactory. A valuable contribution may derive from identification and
descriptive analysis of well-defined subgroups of patients. Clinics, biology, function, gait analysis,
and plantar pressure variables were assessed in 78 patients with diabetes. In 15 of them, the 3D



architecture of the foot bones was characterized by using weight-bearing CT. Patients were grouped


by diabetes type (T1, T2), presence (DN) or absence (DNN) of neuropathy, and obesity. Glycated
Citation: Giacomozzi, C.; Lullini, G.; hemoglobin (HbA1c) and plantar lesions were monitored during a 48-month follow-up. Statistical
Leardini, A.; Caravaggi, P.; Ortolani, analysis showed significant differences between the groups for at least one clinical (combined
M.; Marchesini, G.; Baccolini, L.; Berti, neuropathy score, disease duration, HbA1c), biological (age, BMI), functional (joint mobility, foot
L. Analysis of Clinical Profiles, alignment), or biomechanical (regional peak pressure, pressure-time integral, cadence, velocity)
Deformities, and Plantar Pressure
variable. Twelve patients ulcerated during follow-up (22 lesions in total), distributed in all groups but
Patterns in Diabetic Foot Syndrome.
not in the DNN T2 non-obese group. These showed biomechanical alterations, not always occurring
Appl. Sci. 2021, 11, 11464. https://
at the site of lesion, and HbA1c and neuropathy scores higher than the expected range. Three of
doi.org/10.3390/app112311464
them, who also had weight-bearing CT analysis, showed >40% of architecture parameters outside
Academic Editor: Arkady Voloshin the 95%CI. Appropriate grouping and profiling of patients based on multi-instrumental clinical and
biomechanical analysis may help improve prediction modelling and management of diabetic foot
Received: 15 September 2021 syndrome.
Accepted: 25 November 2021
Published: 3 December 2021 Keywords: prediction models; plantar pressure profiles; diabetes; foot alignment; weight-bearing
CT; neuropathy; glycated hemoglobin
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations. 1. Introduction
Altered plantar pressure patterns are largely debated when investigating diabetic
foot syndrome. In particular, the possible role of abnormal plantar loading in the onset
of the foot ulceration process is frequently examined. The most recent guidelines of the
Copyright: © 2021 by the authors. International Working Group on Diabetic Foot (IWGDF) [1] stated that “high plantar pres-
Licensee MDPI, Basel, Switzerland. sures are a significant independent risk factor for foot ulceration and should therefore
This article is an open access article be avoided” [2,3]. Despite this evidence, predictive models of risky plantar pressure pat-
distributed under the terms and
terns still have to reach general validity and agreement. Several interesting models do,
conditions of the Creative Commons
however, exist. In 2006, Giacomozzi and Martelli [4] used a cluster analysis approach
Attribution (CC BY) license (https://
to correlate the peak pressure curve pattern with ankle joint mobility, lower leg mus-
creativecommons.org/licenses/by/
cle isometric torque, and gait analysis. The model showed moderate-to-good sensitivity
4.0/).

Appl. Sci. 2021, 11, 11464. https://doi.org/10.3390/app112311464 https://www.mdpi.com/journal/applsci

Appl. Sci. 2021, 11, 11464 2 of 16

and specificity to predict foot ulceration, but it was only validated for type 2 diabetes.
Hazari et al. [5] proposed a diabetic foot prediction model based on regression analysis,
with more than 150 variables. The model, which fitted a type 2 population well, mainly re-
lied on diabetes-related clinical variables, a specific grading of neuropathy, anthropometrics
but not body mass, foot structure and alignment, and foot and leg kinematics. Barn et al. [6]
reported gender, body mass, diabetes duration, glycated hemoglobin (HbA1c), vibration
perception threshold (VPT), rotation axis of ankle joint motion, foot deformity, ankle range
of motion, and callus as significant predictors of peak pressure among their population.
Fawzy et al. [7] reported a multivariate logistical regression analysis, performed over a
pooled sample of 100 patients with type 1 (37%) and type 2 (63%) diabetes, where risk
of ulceration was found to be associated with duration of diabetes, smoking, severity of
neuropathy, glycemic control, and high peak pressure values and gradients. The study
did not account for foot motion. Al-Rubeaan et al. [8] modelled risk factors for diabetic
foot complications on the wide cohort (62,681 patients with diabetes) of the Saudi National
Register and showed significant odds ratio for Charcot joints, peripheral vascular dis-
ease, neuropathy, diabetes duration >10 years, insulin use, retinopathy, nephropathy, age
>45 years, cerebral vascular disease, poor glycemic control, coronary artery disease, male
gender, smoking, and hypertension. This study analyzed clinical and biological variables,
demographics, and lifestyle, while no data were available with respect to foot structure
and biomechanics.
With respect to ulcer recurrence, Aan de Stegge et al. [9] recently developed a multi-
variable prediction model addressing all types of recurrent plantar foot ulcers and including
the following risk factors: the presence of a minor lesion, living alone, increased barefoot
peak plantar pressure, longer duration of having a previous foot ulcer, and less variation in
daily stride count. The study included 171 patients with type 1 (~30%) and type 2 (~70%)
diabetes and history of recurrent ulcers, and the model area under the receiver operator
curve was 68%.
With special attention to model diabetic foot plantar pressures by exploiting radiolog-
ical assessment, Guldemond et al. [10] implemented a linear regression model based on
variables extracted from barefoot plantar pressure measurements, radiographic evaluation,
and peripheral neurological, orthopedic, and vascular assessment. The latter consisted of
weight-bearing anterior-posterior and lateral radiographs, which delivered 18 (5 angular
and 13 linear) and 15 (9 angular and 6 linear) measurements, respectively. The model could
only explain about 34% of the variance in the local peak pressure. However, the inclusion
of foot architecture in the model may be of interest, especially now that innovative foot
architecture measurements can be extracted from the weight-bearing CT (WBCT) [11].
The complexity of modeling diabetic foot loading alterations was addressed in Gi-
acomozzi et al. [12]. The authors highlighted the extremely high variability of the dy-
namic plantar loading pattern, also due to the heterogeneity of the patients’ clinical and
bio-mechanical profiles, and suggested a more refined patient stratification, either for
modelling or ulcer risk classification.
The main hypothesis of the present study was that the stratification of patients with
diabetes in subgroups according to type, presence or absence of neuropathy, and presence
or absence of obesity may help reduce the variability of their most relevant characteristics.
As a consequence, profiles peculiar to each group might be better identified for the main
clinical, biological, orthopedic, functional, and biomechanical variables. This study was
then articulated to address three main objectives: (1) to describe patient profiles within
each group and to highlight possible differences; (2) to analyze and interpret the profiles
of those patients who developed lesions during a 48-month follow-up period; and (3) to
explore the possible relevance of the analysis of the 3D foot architecture—delivered by the
weight-bearing CT (WBCT)—conducted on a small subset of type 1 patients.
Appl. Sci. 2021, 11, 11464 3 of 16

2. Materials and Methods

2.1. Participants
From January to December 2016, patients with diabetes referring to the Diabetic
Foot Clinical Center of the S. Orsola-Malpighi Hospital (Bologna, Italy) were invited to
participate in the study. Those who gave informed consent were first screened at the
Diabetic Foot Clinical Center and then examined at the Movement Analysis Laboratory of
the Istituto Ortopedico Rizzoli (Bologna, Italy) within one week. The following information
were collected via the clinical and podiatric screening: biological data (age, gender, body
mass index (BMI), and obesity grade [13]), clinical data (type of diabetes, years of disease
(YOD), glycated hemoglobin (HbA1c) level, peripheral neuropathy grade based on the
Michigan Neuropathy Screening Instrument [14] and the Vibration Perception Threshold
(VPT) measurement, the presence of peripheral artery disease or of other relevant co-
morbidities), and functional and orthopedic data (passive ankle joint mobility [15], hindfoot
alignment, hallux mobility and alignment [15], pain via the visual analogue scale (VAS) and
the Manchester Oxford Foot Questionnaire (MoX) [16]). On the same day of the examination
at the Movement Analysis Laboratory, patients were functionally assessed via gait analysis
according to the experimental protocol detailed in the following as experimental protocol
1 (Section 2.2). Those patients who also gave consent to the WBCT acquisitions were
examined three-to-six months after the overall assessment according to the experimental
protocol 2 detailed in the following (Section 2.3).
Seventy-nine patients were enrolled in total, all without peripheral artery disease
(Ankle-Brachial Index (ABI) > 0.9). Only one type 1 patient was in the obesity range and
was examined but excluded from the analysis by group. The remaining 78 patients were
grouped as follows: type 1 patients with neuropathy (DNT1, 12 patients); type 1 patients
without neuropathy (DNNT1, 15 patients); type 2 patients, not obese and with neuropa-
thy (DNT2-no ob, 11 patients); type 2 patients, with obesity and neuropathy (DNT2-ob,
20 patients); type 2 patients, without obesity or neuropathy (DNNT2-no ob, 7 patients); and
type 2 patients, with obesity and without neuropathy (DNNT2-ob, 13 patients) (Table 1).

Table 1. Clinical and biological description of patients.

ALL DNT1 DNT2-No ob DNT2-ob DNNT1 DNNT2-No ob DNNT2-ob

n (M/F) 79 (39M/40F) 12 (9M/3F) 11 (6M/5F) 20 (11M/9F) 15 (1M/14F) 7 (3M/4F) 13 (8M/5F)
AGE (years) 58.1 ± 12.0 53.1 ± 14.1 67.1 ± 8.8 61.6 ± 6.8 48.3 ± 14.6 65.4 ± 3.9 58.3 ± 8.2
BMI (kg/m2 ) 29.4 ± 6.8 24.8 ± 2.5 25.1 ± 3.1 35.7 ± 5.4 23.6 ± 3.2 25.6 ± 3.3 36.3 ± 3.8
YOD (years) 20.0 ± 12.8 34.2 ± 12.6 18.4 ± 8.6 13.9 ± 7.8 23.6 ± 3.2 12.4 ± 9.0 12.1 ± 6.7
NS-VPT 3.2 ± 1.4 3.8 ± 0.9 4.3 ± 1.0 4.2 ± 1.2 1.7 ± 0.7 2.5 ± 1.3 2.3 ± 0.9
Mean HbA1c (%) * 7.9 ± 1.3 8.4 ± 1.6 7.0 ± 0.8 8.0 ± 1.4 8.3 ± 1.0 7.1 ± 0.3 8.2 ± 1.5
MIN HbA1c (%) * 7.1 ± 1.2 7.7 ± 1.3 6.4 ± 0.5 7.1 ± 1.6 7.8 ± 1.1 6.2 ± 0.3 6.9 ± 1.1
MAX HbA1c (%) * 8.9 ± 1.7 9.4 ± 1.8 8.0 ± 1.7 9.0 ± 1.6 8.8 ± 1.0 8.2 ± 1.0 9.8 ± 2.3
patients with 12 (8M/4F) 2 (2M) 2 (2M) 3 (3M) 3 (3F) 2 (1M/1F)
-
lesions * %: 15 (21/10) %: 17 (22) %: 18 (33) %: 15 (27) %: 20 (21) %: 15 (20)
22 (1 midfoot; 3 (1 forefoot;
3 (1 forefoot; 5 (2 big toe; 3 9 (3 forefoot; 3 2 (1 midfoot;
5 forefoot; 6 1 big toe; 1
number of lesions * 2 10 toes) toes) big toe; 3 toes) 1 toes)
big toe; 10 toes) toes)
r: 0.25 r: 0.45 r: 0.45 r: 0.15
r: 0.28 r: 0.20
Legend: * in the 48-month follow-up; %—percentage with respect to the corresponding cases; r—ratio of the number of lesions divided by
the number of cases in the group.

The design of the statistical analysis was based on the identified number of groups
(6), probability of type I error α = 0.05, power = 0.80, and effect size = 0.5. The estimated
total sample size was 60 (G*Power version 3.1.9.7, Heinrich Heine Universität, Dusseldorf,
Germany). Each patient executed an established gait analysis experimental protocol
(experimental protocol 1, see below). Fifteen of the 27 type 1 patients (7 DNNT1 and
8 DNNT1) also agreed to participate in weight-bearing CT scans and were examined
Appl. Sci. 2021, 11, 11464 4 of 16

(experimental protocol 2 below). All patients were followed up for the following 48 months
at the Diabetic Foot Clinical Center, where the ulcer prevention program was implemented
on the basis of the IWGDF Guidelines [1]. HbA1c was also measured every six months
from the overall assessment. Patients who developed lesions (PWL) were analyzed both as
an additional group and individually.
Approval was obtained by the metropolitan ethical committee for experimental proto-
col 1 and by the local Ethical Committee (Prot. IOR 7685 28 July 2017) for experimental
protocol 2. Relevant informed consents were signed by participants in the study.

2.2. Experimental Protocol 1: Data Collection and Analysis

Multi-instrumental gait analysis was performed by exploiting an established pressure-
force-kinematics technique [17] so as to obtain highly reliable plantar regions of interest
(ROIs). While ROI identification is often based on the geometry of the acquired pressure
footprint, whenever proper stereophotogrammetry for foot kinematics and a suitable multi-
segmental foot model are reliably used, ROIs can be better identified by exploiting the
position of foot and ankle anatomical markers. This reliable anatomical masking allows
the best matching between plantar loaded areas and anatomical structures of the foot to be
achieved, even in the presence of abnormal or incomplete footprints [18,19]. In the present
study, the Rizzoli Foot Model [20] and the anatomical masking were used to separate
the hindfoot from the midfoot on the basis of the midtarsal joint (Chopart’s joint), the
midfoot from the forefoot on the basis of the Lisfranc joint, the metatarsal area of the
forefoot from the toes based on the arch of the metatarsal heads and the positions of the
first metatarsal head and the base of the hallux phalanx, and the hallux from the other
toes on the basis of the alignment of the first metatarsal. The experimental protocol of
this study relied on pressure patterns and kinematic data acquired during barefoot level
walking at a self-selected speed. A capacitive sensor platform (EMED® q-100, novelGmbH ,
Munich, Germany; 4 sensors/cm2 ; range 0–1270 kPa; 100 Hz) was synchronized with an
eight-camera 3D motion tracking system (Vicon® , Oxford, UK) by off-line aligning the
signal from the pressure platform to the signal from a force plate rigidly fixed underneath
and acquired simultaneously with the tracking system. The established marker-set of
the Rizzoli Foot Model [20] was used to track the multi-segment foot kinematics. Five
consistent full footprints were collected for each patient and foot. The anatomical masking
procedure was automatically applied to each foot (EMED-associated software packages by
novelGmbH , Munich, Germany) to identify the five ROIs, namely the hindfoot, the midfoot,
the forefoot, the big toe, and the other toes [17]. Main pressure-related parameters were
extracted for each ROI by means of the same dedicated software packages and averaged
over repetitions within each foot. Regional Peak Pressure (PP, kPa) and Pressure-Time
Integral (PTI, kPa·s) were included in the analysis for a total of 10 parameters for each foot.
The dominant (D) and non-dominant (ND) limbs were analyzed separately.

2.3. Experimental Protocol 2: Data Collection and Analysis

Both feet of each of the 15 type 1 patients were CT scanned (OnSight 3D Extremity
System, Carestream, Rochester, NY, USA) in single-leg upright posture. Patients were
instructed to put full weight on the analyzed foot and to use the other contacts just
for equilibrium. For the preliminary study [11], only one randomly selected foot was
analyzed for each patient. For this foot scan, virtual slicing set at a 0.26 mm distance
was performed and the resulting DICOM file was then processed in Amira™ (Thermo
Fisher™ Scientific, Waltham, MA, USA) to define a corresponding 3D model for each of
the relevant bones. These files in STL format were imported in Matlab® (Mathworks Inc.,
Natick, MA, USA), where dedicated algorithms made it possible to define an appropriate
foot anatomical reference frame and to realign bone segments to this frame. Absolute and
relative metatarsals and phalanxes inclinations were calculated in the three anatomical
planes and in 3D, i.e., with respect to the floor. Absolute and relative heights of metatarsals,
Appl. Sci. 2021, 11, 11464 5 of 16

phalanxes, and cuboid and navicular bones were also included in the analysis, for a total of
84 variables for each foot.

2.4. Data Analysis and Statistics

Descriptive statistics were done on the following variables, grouped as follows:
• Passive joint mobility and alignment (all measured in degrees) [15]: maximum passive
ankle dorsiflexion (TT dors); maximum passive ankle plantar flexion (TT plant); maxi-
mum passive ankle inversion (TT supin); maximum passive ankle eversion (TT pron);
maximum passive first metatarsophalangeal joint extension (I MTP ext); maximum
passive first metatarsophalangeal joint flexion (I MTP flex); hindfoot inclination in the
frontal plane (hindfoot incl); hallux inclination in the transverse plane (hallux incl);
• Biology and clinics: age (years); body mass index (BMI, kg/m2 ); years of disease
(YOD, years); combined neuropathy score (NS-VPT, relative unit), which combines
scores from the MNSI with the vibration perception threshold (VPT, volts) at both
limbs [11]; mean glycated hemoglobin (Mean HbA1c, %) averaged over the 48-month
follow-up; minimum HbA1c (MIN HbA1c, %) and maximum HbA1c (MAX HbA1c,
%) recorded over the 48-month follow-up; pain visual analogue scale questionnaire
(VAS, 10-points score) for each limb; Manchester Oxford Foot Questionnaire (MoX,
16 items, max score 64) [16];
• Overall gait performance: dynamic arch index (AI, relative unit), cadence (cad,
steps/min), foot contact time (CT, ms), velocity (vel, m/s);
• Plantar peak pressure distribution: peak pressure during gait (PP, kPa) at the hindfoot,
midfoot, forefoot, big toe, and toes; dominant (D) and not-dominant (ND) limbs were
analyzed separately; and
• Plantar pressure-time integral distribution: pressure-time integral during gait (PTI,
kPa·s) at the hindfoot, midfoot, forefoot, big toe, and toes; dominant (D) and not-
dominant (ND) limbs were analyzed separately.
The whole group of patients (ALL), the six clinical subgroups, and the patients with
lesions’ (PWL) group were examined. One-way ANOVA was implemented to highlight
differences among these groups (p < 0.05, adjusted for Tukey post-hoc comparisons). The
coefficient of variation (CV) was calculated for each variable and group, and averaged
(mCV) within each group of variables. The profile of each patient with lesions was finally
compared with those of the corresponding group.
Confidence intervals (95% CIs) were calculated for each weight-bearing CT-related
variable for the two subgroups of type 1 patients (with (DNT1) and without (DNNT1)
neuropathy. Those intervals allowed the exploration of changes in the small subset of
patients with lesions who also underwent the WBCT examination. The R Foundation
environment was used for the statistical analysis.

3. Results
Twelve patients (8M/4F; age 58.2 ± 10.3; BMI 27.9 ± 6.3; YOD 24.4 ± 13.8; NS-VPT:
3.8 ± 1.7; mean HbA1c: 8.3 ± 1.6; MIN HbA1c: 7.7 ± 1.5; MAX HbA1c 9.1 ± 1.7) developed
a total of 22 plantar lesions during the follow-up (Table 2).
High variability and, consequently, no statistically significant differences were found
between the entire group of patients and the group of patients with lesions (Figure 1).
Statistically significant differences were found among the six groups of patients namely
type 1 with (DNT1) and without (DNNT1) neuropathy, non-obese type 2 with (DNT2-
no ob) and without (DNNT2-no ob) neuropathy, and obese type 2 with (DNT2-ob) and
without (DNNT2-ob) neuropathy; these differences were found for one or more groups of
variables as summarized in Table 3. The profiles and patterns of investigated variables for
each group of patients are plotted in Figures 2–6 as follows: Figure 2 shows the profiles
of the passive joint mobility and the alignment parameters, Figure 3 shows the profiles
of the biological and clinical parameters, Figure 4 illustrates the overall gait performance
parameters, and Figures 5 and 6 report the patterns of the regional plantar Peak Pressure
Appl. Sci. 2021, 11, 11464 6 of 16
Appl. Sci. 2021, 11, x FOR PEER REVIEW 8 of 18

(PP, kPa) and Pressure-Time Integral (PTI, kPa·s) parameters, respectively. Variability
BMI;
within each group remained high for some variables and groups, as is for the overall gait
DNNT2-no ob performance in neuropathic groups (Figure 4), and for pressure-related PTI midfoot
regional D and
parameters
ND
in the DNT2 groups (Figures 5 and 6). Conversely, variability significantly decreased for
DNNT2-ob passive mobility and alignment in DNT1 and non-obese DNNT2 (Figure 2), biological and
Legend: D: dominant limb; clinical
ND: non-dominant
parameterslimb; DN:
in all diabetes
groups and neuropathy;
(Figure DNN: diabetes without
3), and pressure-related regionalneuropathy;
parameters in
T1: type 1 diabetes; T2: typeDNT1
2 diabetes; ob: obese; no ob: non-obese.
and all non-neuropathic groups (Figures 5 and 6).

60
Passive joint mobility and alignment (°) 10
Biology and clinics Overall gait performance
0.8
8
0.7
40 0.6
6
0.5
4
0.4
20
2 0.3
mCV: 0.27 mCV: 0.28 0.2 mCV: 0.19 mCV: 0.19
mCV: 0.47 mCV: 0.42 0
0

MAX HbA1c
MIN HbA1c
BMI ·0.1
MOX ND ·0.2

AGE ·0.1

YOD ·0.1
MOX D ·0.2

MEAN HbA1c
VAS D

NS-VPT

vel D (m/s)
VAS ND

vel ND (m/s)
CT ND (s)
AI ND

(spm ·0.01)

(spm ·0.01)

CT D (s)
AI D

cad D

cad D
Appl. Sci. 2021, 11, x FOR PEER REVIEW
Appl. Sci. 2021, 11, x FOR PEER REVIEW
Appl. Sci.
Appl. Sci. 2021, 11,
11, x FOR
FOR PEER REVIEW
REVIEW
Regional Sci. 2021,
PP (kPa)
Appl. 2021, 11, x
x FOR PEER
PEER REVIEW Regional PTI (kPa*s)
Appl. Sci. 2021, 11, x FOR PEER REVIEW
800 300

600
250
3. Results ALL m
200
3.
3. Results
Twelve patients (8M/4F; age 58.2 ± 10.3; BMIALL 27.9
PWL m
± 6.3; YOD 24.4 ± 13.8;
400 150 3. Results
Results m ± sd
100 3. 1.7;
± Results
mean
Twelve HbA1c:
patients 8.3 ± 1.6;
(8M/4F; MIN
age HbA1c:
58.2 ± 10.3;7.7
BMI± 1.5;
27.9 MAX
± 6.3;HbA1c
YOD 24.49.1 ±±13.8;
1.7)
200
50
Twelve
Twelve patients
patients (8M/4F;
(8M/4F; age
age 58.2
58.2 ±
± 10.3;
10.3; BMI
BMI 27.9
m±sd ±
27.9
LPWL ± 6.3;
6.3; YOD
YOD 24.4
24.4 ±± 13.8;
13.8;
total
±
± 1.7;of 22
mean
Twelve plantar
HbA1c: lesions
patients 8.3 ± during
1.6;
(8M/4F; MIN
age the follow-up
HbA1c:
58.2 ± 10.3;7.7
BMI(Table
± 1.5;
27.9 2).
MAX
± 6.3;HbA1c
YOD 9.1
24.4 ±± 1.7)
13.8;
0
mCV: 0.44 mCV: 0.55 0 ± 1.7;
mCV: 0.52
1.7; meanmCV: HbA1c:
mean 0.59
HbA1c: 8.3
8.3 ±± 1.6;
1.6; MIN
MIN HbA1c:
HbA1c: 7.7 7.7 ±
± 1.5;
1.5; MAX MAX HbA1c
HbA1c 9.19.1 ±± 1.7)
1.7)
total
±
total High
1.7;of
of 22
mean
22 variability
plantar
HbA1c:
plantar and,
lesions
8.3
lesions± consequently,
during
1.6; MIN
during the
theHbA1c:no
follow-up
follow-upstatistically
7.7 (Table
± 1.5;
(Table MAXsignificant
2).
2). HbA1c difference
9.1 ± 1.7)
total of 22 plantar lesions during the follow-up (Table 2).
total High
between of
High 22
theplantar
entire
variabilitylesions
group
and, during
of the
patients
consequently, follow-up
and nothe (Table
group
statistically of 2).
patients with
significant lesions
difference (
High variability
variability and,
and, consequently,
consequently, no no statistically
statistically significant
significant difference
difference
Figure 1.1. Profiles
Profiles and
and patterns
patternsof
ofthe
theinvestigated between
investigatedparameters Highthe
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within
the eachgroup
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and the
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are plottedwith
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group of patients and values
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for the entire group of patients (ALL) and Table
for the2.subgroup
Description
between the
of ofentire
lesionswith
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group occurred
of 1–48and
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for the entire group of patients (ALL) and for the subgroup of patients with lesions (PWL), for the dominant (D) and the
non-dominant (ND) limb. Few parametersTable Table 2.‘biology
in the2. Description of
andof lesions
clinics’ that
and inoccurred 1–48gait
the ‘overall months (m) after
after group
performance’ the assessment.
assessment.
have
non-dominant (ND) limb. Few parameters in Table 2. Description
Description
the ‘biology of lesions
lesions
and clinics’ that
and in theoccurred
that occurred 1–48 months
months (m)
1–48performance’
‘overall gait after the
(m) group the assessment.
have been
been scaled according to the reported factor for better
Table Patients
readability
2. Description of the plot.
of lesions The mean1–48
that occurred coefficient
monthsof variation
(m) after the(mCV) is
assessment.
scaled according to the reported factor for better readability of the plot. The mean coefficient of variation (mCV) is reported
Group
reported for each group and plot. Cases Patients
with
Patients Description of Lesions
for each group and plot. Patients
Group
Group Cases
Cases with
Patients
Lesions
with Description
Description of Lesions
Group Cases with Description of
of Lesions
Lesions
Group
Table 2. Description Cases Lesions
with 1–48 monthsDescription
of lesions that occurred
Lesions (m) after theof Lesions
assessment.
Lesions L1 (M): D (toes, m24) and ND (forefoot, m36)
Group DNT1
Cases 12 (9M/3F) 2Lesions
Patients with(2M/0F)
Lesions Description
L1 (M): of
L2 D Lesions
(toes, m24) and ND (forefoot, m36)
DNT1
DNT1 12
12 (9M/3F) 2 (2M/0F) L1 (M):
L1 (M): D D (toes,
(toes, m36)
m24)
m24) and
and NDND (forefoot,
(forefoot, m36)
m36)
DNT1 12 (9M/3F)
(9M/3F) 22 (2M/0F)
(2M/0F) L1
L1
L2 (M):
(M): D D (toes,
(toes, m24)m24)
andand
m36) NDND (forefoot,
(forefoot, m36) m36)
DNT1 12 (9M/3F)
DNT1 2 (2M/0F)2 (2M/0F)
12 (9M/3F) L2
L2 (M):
(M): D D (toes,
(toes,toe,m36)
m36)
L1
L2 (M):
(M):DD
L2(M): D (big
(toes,
(toes, m36) m48; toes, m48)
m36)
DNT2 no ob 11 (6M/5F) 2 (2M/0F)
L1
L2 (M):
(M): D (big toe, m48; toes,
toes, m9m48)
DNT2
DNT2 no
no ob 11 (6M/5F) 2 (2M/0F) L1
L1 (M):DD
L1(M): D (big
(big
(big toe,toe,
toe, m36;
m48;
m48;
m48; m48)m48)
toes,toes, and m36)
m48)
DNT2 no ob DNT2 no ob
11 (6M/5F)
ob 11
11 (6M/5F)
2 (2M/0F)2
(6M/5F) 2 (2M/0F)
(2M/0F) (M): D
L1 (M):
L2 D (big
(big toe,
toe, m36; toes, m9
m48; toes, m48)
and m36)
DNT2 no ob 11 (6M/5F) 2 (2M/0F) L2 (M):
(M):DD
L2(M):
L2 D (big
(big
(big toe,toe,
toe, m36;
m36;
m36; toes,
toes,
toes,m48)
m9 andm9 and
and m36)
m9 m36) m36)
L1
L2 (M):
(M): D D (toes,
(big toe,m9 and
m36; toes, m9 and m36)
DNT2 ob 20 (11M/9F) 3 (3M/0F) L1
L1
L1 (M):
L2(M):
(M): DD (toes,
(toes,
ND m9m9andand
(forefoot, m9m48)
m48) and m24 and m48)
L1 (M): D D (toes,
(toes, m9
m9 and
and m48)
m48)
DNT2 ob 20 (11M/9F) 3 (3M/0F) L1
L2
L2
L3 (M):
(M): ND D
ND (toes, m9
(forefoot,
(forefoot, and
m6m9
toe, m9 m48)
andand
and m24 m24
and and
m48) m48)
DNT2 ob DNT2 ob
20 (11M/9F)
DNT2 ob 20
20 (11M/9F)
3 (3M/0F)3
(11M/9F) 3 (3M/0F)
(3M/0F) L2 (M):
L2 (M): D ND
ND (big(forefoot,
(forefoot, m9
m9 and
andm24 and
m24
m24 m48)
and
and and ND
m48)
m48)
DNT2 ob 20 (11M/9F) 3 (3M/0F) L2
L3
L3 (M):
(M): DD ND
D
(big (forefoot,
(big toe,
toe, m6m6m6 m9
and and
and m24m24m24m24
and and m48)
m48)
and and ND
and m48)m48) ND
L3
L3 (M): (big
(big toe,
(M):DD(toes, toe, m6 and
and m24 and and m48) and
and ND
L1 (F):
ND (toes, m24) m24)
L3 (M): D (big toe, m6 and m24 and m48) and ND
DNNT1 15 (1M/14F) 3 (0M/3F) L1
L2 (F):
(F): D (toes, m24)
L1
L1 (F):DD
L1(F): D (big
(toes,
(toes,
(toes, toe,
m24) m36)
m24)
m24)
DNNT1 15 (1M/14F)
3 (0M/3F)3 L1 (F): D (toes, m24)
DNNT1 15 (1M/14F)
DNNT1
DNNT1 15
15 (1M/14F)
(1M/14F) 33 (0M/3F)
(0M/3F)
(0M/3F)
L2
L3
L2
L2 (F):
(F):
L2(F):
D
(F):DND
D
D
(big
(big
(big
(big
toe,
toe,
toe, m36)
(forefoot,
m36)
m36)
toe, m36)m36)
DNNT1 15 (1M/14F) 3 (0M/3F) L2
L3 (F): D
ND (big toe,
(forefoot,m36)
m36)
L3
L3 (F):
L3(F): ND
(F):ND
ND (forefoot,
(forefoot,
(forefoot, m36)m36)
m36)
DNNT2 no ob 7 (3M/4F) - L3 (F): ND (forefoot, m36)
DNNT2 no ob 7 (3M/4F) -
DNNT2
DNNT2 no ob 77 (3M/4F) --
DNNT2 nono ob
ob 7 (3M/4F)
(3M/4F) - L1(M):
L1 (M):ND
ND (toes,
(toes, m48)
m48)
DNNT2 ob DNNT2 no ob
13 (8M/5F)
DNNT2 ob 7 (3M/4F)
2 (1M/1F)2
13 (8M/5F) - (1M/1F)
L1
L2
L2 (M):
(F): ND
DD (toes,
(midfoot, m48)
m24)
DNNT2
DNNT2 ob 13 (8M/5F) 22 (1M/1F) L1(F):
L1 (M):
(M): (midfoot,
ND
ND (toes,m24)
(toes, m48)
m48)
Total DNNT2 ob
ob 13
13 (8M/5F)
(8M/5F) 2 (1M/1F)
12 (8M/4F) (1M/1F) L1
22 (1L2 (F): D (midfoot,m48)
(M):
midfoot;ND
5 (toes,
forefoot; 6m24)
big toe; 10 toes)
DNNT2 ob 13 (8M/5F) 2 (1M/1F) L2
L2 (F):
(F): D
D (midfoot,
(midfoot, m24)
m24)
Total 12 (8M/4F)
Legend: D: dominant limb; ND: non-dominant limb; DN: diabetes and neuropathy; DNN: 22 (1L2midfoot;
diabetes 5 forefoot;
(F):without neuropathy;
D (midfoot, 6T1:
m24) bigtype
toe;1 diabetes;
10 toes)
T2: type 2 diabetes; ob:Total 12 (8M/4F)
obese; no ob: non-obese. Colors are associated 22
with the profiles (1
and midfoot;
patterns in 5 forefoot;
Figures 2–6. 6 big toe; 10 toes)
Total 12
12 (8M/4F)
Legend: D: dominant limb; ND: non-dominant
Total (8M/4F) limb;22 (1
(1 midfoot;
22DN: 55 forefoot;
diabetes and
midfoot; 66 big
neuropathy;
forefoot; toe;
toe; 10
bigDNN: toes)
diabetes
10 toes) without neu
Total
T1: type D:
Legend: 1 diabetes;
dominant T2: typeND:
limb; 12 (8M/4F)
2 diabetes; ob: obese;
non-dominant 22DN:
no
limb; (1 non-obese.
ob: midfoot; 5Colors
forefoot;
diabetes and are 6 bigDNN:
toe; 10
associated
neuropathy; toes)
with the profiles
diabetes without and
neu
Legend:
Legend: D: dominant
dominant limb;
D:2–6. limb; ND:
ND: non-dominant
non-dominant limb;
limb; DN:
DN: diabetes
diabetes and
and neuropathy;
neuropathy; DNN:
DNN: diabetes
diabetes without
without neu
neu
in
T1:Figures
type
Legend: 11 diabetes;
D: dominant T2: type
limb; 22 diabetes;
ND: ob:
non-dominantobese; no
limb; ob:
DN: non-obese.
diabetes Colors
and are associated
neuropathy; DNN: with the
diabetes profiles
without and
neu
T1: type diabetes; T2: type diabetes; ob: obese; no ob: non-obese. Colors are associated with the profiles
T1: type 1 diabetes; T2: type 2 diabetes; ob: obese; no ob: non-obese. Colors are associated with the profiles and
and
in
T1:Figures
in type 1 2–6.
Figures diabetes; T2: type 2 diabetes; ob: obese; no ob: non-obese. Colors are associated with the profiles and
2–6.
in Figures 2–6.
in Figures 2–6. Statistically significant differences were found among the six groups group
namely type 1 with
Statistically (DNT1) differences
significant and withoutwere
(DNNT1)
found neuropathy, non-obese
among the six groups
Appl. Sci.
Appl.2021, 11, 11464
Sci. 2021, 11, x FOR PEER REVIEW 9 of 18 7 of 16

Passive joint mobility and alignment (°)

70 70 DNNT1
60
DNT1 60

50 50

40 40

30 30

20 20

10 10 mCV: 0.41
mCV: 0.33
0 0

70 70

60
DNT2 – no ob DNNT2 – no ob
60

50 50

40 40

30 30

20 20

10 10

0
mCV: 0.43 mCV: 0.29
0

70 70

60 DNT2 – ob 60 DNNT2 – ob
50 50

40 40

30 30

20 20

10 10

0
mCV: 0.40 0
mCV: 0.47

Legend:
group mean ± sd; pat #1 with lesions (L1); pat #2 with lesions (L2); pat #3 with lesions (L3)
D: dominant limb; ND: non-dominant limb; DN: diabetes and neuropathy; DNN: diabetes without neuropathy;
T1: type 1 diabetes; T2: type 2 diabetes; ob: obese; no ob: not obese

Figure 2. Profiles
Figure of the
2. Profiles passive
of the joint
passive jointmobility andalignment
mobility and alignment parameters
parameters (◦ ) within
(°) within each each
groupgroup of patients.
of patients. Mean± values
Mean values
± SD are plotted for each group, with the profiles of patients with lesionstoadded
SD are plotted for each group, with the profiles of patients with lesions added the plotto
of the
the group each
plot of theofgroup
them belongs
each of them
to.
belongs to.

Table 3. Statistically significant differences between groups of patients (one-way ANOVA, p < 0.05 adjusted for Tukey
multiple comparisons).

DNT1 DNT2-no ob DNT2-ob DNNT1 DNNT2-no ob DNNT2-ob

TT dors ND;
hindfoot incl ND;
BMI; YOD;
AGE; YOD; NS-VPT;
DNT1 NS-VPT YOD
YOD CT ND; PTI midfoot D
vel ND; and ND
PTI midfoot D
and ND
BMI; AGE;
NS-VPT; NS-VPT;
DNT2-no ob PTI hindfoot D; NS-VPT;
PTI forefoot D PTI forefoot D
PTI midfoot D PTI forefoot D
Appl. Sci. 2021, 11, 11464 8 of 16

Table 3. Cont.

DNT1 DNT2-no ob DNT2-ob DNNT1 DNNT2-no ob DNNT2-ob

MOX D and ND;
AGE;
YOD;
NS-VPT;
cad D and ND;
CT D and ND;
vel D and ND;
NS-VPT;
DNT2-ob PP midfoot D; NS-VPT
PTI midfoot D
PP forefoot D;
PTI hindfoot D
and ND;
PTI midfoot D
and ND;
PTI forefoot D
and ND
BMI;
AGE; YOD;
DNNT1 YOD; vel D;
MIN HbA1c PTI midfoot D
and ND
BMI;
DNNT2-no ob PTI midfoot D
and ND
DNNT2-ob Appl. Sci. 2021, 11, x FOR PEER REVIEW 10 of 18
Legend: D: dominant limb; ND: non-dominant limb; DN: diabetes and neuropathy; DNN: diabetes without neuropathy; T1: type 1 diabetes;
T2: type 2 diabetes; ob: obese; no ob: non-obese.

Biological and clinical parameters

12
DNT1 12
DNNT1
10 10

8 8

6 6

4 4

2 2

mCV: 0.21 mCV: 0.23

0 0

12
DNT2 – no ob 12 DNNT2 – no ob
10 10

8 8

6 6

4 4

2 2

0
mCV: 0.19 mCV: 0.22
0

12 DNT2 – ob 12 DNNT2 – ob
10 10

8 8

6 6

4 4

2 2

mCV: 0.23 mCV: 0.24

0 0
VAS D

MAX HbA1c
BMI ·0.1

MIN HbA1c
MOX ND ·0.2

AGE ·0.1

YOD ·0.1

NS-VPT

MEAN HbA1c
VAS ND

MOX D ·0.2
VAS D

MAX HbA1c
BMI ·0.1

MIN HbA1c
MOX ND ·0.2

AGE ·0.1

YOD ·0.1

NS-VPT

MEAN HbA1c
VAS ND

MOX D ·0.2

Legend:
group mean ± sd; pat #1 with lesions (L1); pat #2 with lesions (L2); pat #3 with lesions (L3)
D: dominant limb; ND: non-dominant limb; DN: diabetes and neuropathy; DNN: diabetes without neuropathy;
T1: type 1 diabetes; T2: type 2 diabetes; ob: obese; no ob: not obese

Figure 3. Figure
Profiles 3.
of the biological
Profiles andbiological
of the clinical parameters within parameters
and clinical each group ofwithin
patients.each
Measurement
group ofunits for eachMeasure-
patients.
variable are reported on the horizontal axis close to each parameter label (arch index (AI) is reported in relative unit). For
Manchester Oxford Foot Questionnaire (MOX), AGE, BMI, and years of disease (YOD), a scale factor was necessary in
order to enhance the readability of the plot. Mean values ± SD are plotted for each group, with the profiles of patients with
lesions added to the plot of the group each of them belongs to.
Appl. Sci. 2021, 11, 11464 9 of 16

ment units for each variable are reported on the horizontal axis close to each parameter label (arch
index (AI) is reported in relative unit). For Manchester Oxford Foot Questionnaire (MOX), AGE, BMI,
and years of disease (YOD), a scale factor was necessary in order to enhance the readability11ofofthe
Appl. Sci. 2021, 11, x FOR PEER REVIEW 18
plot. Mean values ± SD are plotted for each group, with the profiles of patients with lesions added
to the plot of the group each of them belongs to.

Overall gait performance

0.9 DNT1 0.9

DNNT1
0.8 0.8

0.7 0.7

0.6 0.6

0.5 0.5

0.4 0.4

0.3 0.3

0.2 0.2

0.1 0.1
mCV: 0.19 mCV: 0.14
0.0 0.0

0.9 DNT2 – no ob 0.9 DNNT2 – no ob

0.8 0.8

0.7 0.7

0.6 0.6

0.5 0.5

0.4 0.4

0.3 0.3

0.2 0.2

0.1 0.1
mCV: 0.21 mCV: 0.16
0.0 0.0

DNT2 – ob
0.9 0.9 DNNT2 – ob
0.8 0.8

0.7 0.7

0.6 0.6

0.5 0.5

0.4 0.4

0.3 0.3

0.2 0.2

0.1 0.1
mCV: 0.19 mCV: 0.14
0.0 0.0
CT ND (s)

vel D (m/s)
AI ND

CT D (s)

vel ND (m/s)

CT ND (s)

vel D (m/s)
(spm ·0.01)

(spm ·0.01)
AI D

AI ND

CT D (s)

vel ND (m/s)
(spm ·0.01)

(spm ·0.01)
AI D
cad D

cad D

cad D

cad D

Legend:
group mean ± sd; pat #1 with lesions (L1); pat #2 with lesions (L2); pat #3 with lesions (L3)
D: dominant limb; ND: non-dominant limb; DN: diabetes and neuropathy; DNN: diabetes without neuropathy;
T1: type 1 diabetes; T2: type 2 diabetes; ob: obese; no ob: not obese

Figure 4.
Figure Overall gait
4. Overall gait performance
performanceparameters
parameterswithin
withineach
eachgroup
group of
of patients.
patients. Measurement
Measurementunitsunitsfor
foreach
eachvariable
variableare
are
reported
reported on the horizontal axis close to each parameter label. For cadence (cad, measured in step per minute (spm)),
horizontal axis close to each parameter label. For cadence (cad, measured in step per minute (spm)), a a scale
factorfactor
scale was necessary in order
was necessary to enhance
in order the readability
to enhance of the plot.
the readability Mean
of the Mean ±
plot.values SD are
values ± plotted for eachfor
SD are plotted group,
eachwith the
group,
with the profiles of patients with lesions added to the plot of the group each of them
profiles of patients with lesions added to the plot of the group each of them belongs to. belongs to.
Appl.
Appl.Sci.
Sci.2021,
2021,11,
11,x11464
FOR PEER REVIEW 1210ofof1816

Regional PP (kPa)

1000
DNT1 1000
DNNT1
800 800

600 600

400 400

200 200

0
mCV: 0.44 0
mCV: 0.36

1000 DNT2 – no ob 1000 DNNT2 – no ob

800 800

600 600

400 400

200 200

0
mCV: 0.63 0
mCV: 0.44

1000
DNT2 – ob 1000 DNNT2 – ob
800 800

600 600

400 400

200 200

0
mCV: 0.61 0
mCV: 0.42

Legend:
group mean ± sd; pat #1 with lesions (L1); pat #2 with lesions (L2); pat #3 with lesions (L3)
D: dominant limb; ND: non-dominant limb; DN: diabetes and neuropathy; DNN: diabetes without neuropathy;
T1: type 1 diabetes; T2: type 2 diabetes; ob: obese; no ob: not obese

Patterns
Figure5.5.Patterns
Figure of the
of the regional
regional plantar
plantar PeakPeak Pressure
Pressure (PP, kPa)
(PP, kPa) parameters
parameters withinwithin each group
each group of patients.
of patients. Mean
Mean values
±values
SD are±plotted
SD arefor eachfor
plotted group,
each with
group,thewith
patterns of patients
the patterns with lesions
of patients (PWL)(PWL)
with lesions addedadded
to thetoplot
the of the
plot ofgroup eacheach
the group of
them belongs to. For each PWL pattern, a full circle has been added in correspondence with the site of lesion.
of them belongs to. For each PWL pattern, a full circle has been added in correspondence with the site of lesion. An empty An empty
circle
circlehas
hasalso
alsobeen
beenreported
reportedinincase
caseofoflesions
lesionsthat
thatoccurred
occurredbefore
beforethe
theclinical
clinicaland
andfunctional
functionalassessment.
assessment.

Figures 2–6 show data for single patients with lesions—and not as a group—with each
one superimposed to the corresponding average group data. Despite the high heterogeneity
of the variable values, it is worth noticing that, when compared with their group the
following was observed: (a) all patients with lesions showed at least one altered profile or
pattern (Figures 2–6); (b) type 1 patients with lesions, either with or without neuropathy,
showed higher HbA1c levels during the follow-up period (Figure 3); (c) contact time was
longer in several patients with lesions (Figure 4); and (d) in some cases, pressure-related
regional parameters were out of the expected range either in correspondence with lesions
or in different ROIs (Figures 5 and 6).
Three type 1 patients with lesions also underwent the weight-bearing CT examina-
tion, 2 with (DNT1) and 1 without (DNNT1) neuropathy. This measure of foot architec-
ture showed high variability within the two subsets of examined patients (7 DNT1 and
 Appl. Sci. 2021, 11, 11464 11 of 16

8 DNNT1) [11]. However, a high percentage of variables were found out of the 95% confi-
dence intervals in each anatomical plane and in 3D (Figure 7). In particular, one patient
with lesions in DNT1 had 60% of variables in the transverse plane over the confidence
Appl. Sci. 2021, 11, x FOR PEER REVIEW 13 of 18
interval, and the patient with lesion in DNNT1 had ≈50% of variables in 3D below the
confidence interval.

Regional PTI (kPa·s)

400
400
DNT1 DNNT1
350 350

300 300

250 250

200 200

150 150

100 100

50 50

0
mCV: 0.52 0
mCV: 0.40

400
DNT2 – no ob 400
DNNT2 – no ob
350 350

300 300

250 250

200 200

150 150

100 100

50 50

0
mCV: 0.64 0
mCV: 0.49

400 DNT2 – ob 400

DNNT2 – ob
350 350
300 300

250 250

200 200

150 150

100 100

50 50

0
mCV: 0.58 0
mCV: 0.43

Legend:
group mean ± sd; pat #1 with lesions (L1); pat #2 with lesions (L2); pat #3 with lesions (L3)
D: dominant limb; ND: non-dominant limb; DN: diabetes and neuropathy; DNN: diabetes without neuropathy;
T1: type 1 diabetes; T2: type 2 diabetes; ob: obese; no ob: not obese

Patternsof
Figure6.6.Patterns
Figure of the
the regional
regional Pressure-Time
Pressure-TimeIntegral
Integral(PTI, kPa
(PTI, ·s) parameters
kPa· s) parameterswithin eacheach
within group of patients.
group MeanMean
of patients. values
values
± SD ±are
SDplotted
are plotted for group,
for each each group, withpatterns
with the the patterns of patients
of patients with lesions
with lesions (PWL)(PWL)
addedadded
to theto theofplot
plot the of the group
group each of
each
themof belongs
them belongs
to. Forto. ForPWL
each each pattern,
PWL pattern, a full circle
a full circle has added
has been been added in correspondence
in correspondence with
with the theofsite
site of lesion.
lesion. An
An empty
empty circle has also been reported in case of lesions that occurred before the clinical and functional
circle has also been reported in case of lesions that occurred before the clinical and functional assessment. assessment.
Appl. Sci. 2021, 11, x11464
FOR PEER REVIEW 12 of 18
14 16

WBCT parameters in patients with lesions: % of parameters outside the 95% confidence interval

Sagittal plane
DNT1-L1-< 95%CI
60.0

50.0 DNT1-L1-> 95%CI

40.0

30.0
DNT1-L2-< 95%CI
20.0

10.0 DNT1-L2-> 95%CI

3D 0.0 Frontal plane

DNNT1-L1-< 95%CI

DNNT1-L1> 95%CI

Transverse plane

7. Weight-bearing
Figure 7.
Figure Weight-bearingCT CTparameters
parametersin three patients
in three withwith
patients lesions: % of %
lesions: parameters outsideoutside
of parameters the 95%the
confidence interval
95% confidence
of each parameter,
interval for the DNT1
of each parameter, (7 patients)
for the DNT1 (7and the DNNT1
patients) (8 DNNT1
and the patients)(8
subgroups. For each parameter
patients) subgroups. For eachand patient with
parameter and
patient withnumber
lesion, the lesion, the number
of values of values
above above and
and below below the
the interval interval
have beenhave beenseparately.
counted counted separately.
The countThe count is reported
is reported for each
for each anatomical
anatomical plane and plane and3D
for the forparameters.
the 3D parameters.

4.
4. Discussion
Discussion
Diabetic syndromehas
Diabetic foot syndrome haslong
longbeen
been investigated,
investigated, since
since it represents
it represents a majora major
com-
plication of diabetes
complication of diabetes mellitus [21,22].
mellitus The
[21,22]. Thedisease
diseaseisisassociated
associatedwith withvery
very high
high clinical
and economic
and economic burden
burden [23], a strong negative impact on quality of life [24], and high rates
of hospitalization
of hospitalization in in type
type 2 diabetes [25]. The The International
International Working
Working Group on Diabetic
Foot (IWGDF) defined this syndrome as “infection, ulceration, oror
Foot (IWGDF) defined this syndrome as “infection, ulceration, destruction
destruction of of tissues
tissues of
of the
the foot foot
of of a personwith
a person withcurrently
currentlyororpreviously
previouslydiagnosed
diagnosed diabetes
diabetes mellitus,
mellitus, usually
accompanied by
accompanied byneuropathy
neuropathyand/orand/orperipheral
peripheralarterial
arterialdisease
diseasein the lower
in the extremity”
lower extremity”[26].
Besides
[26]. neuropathy
Besides neuropathy[25,27] and different
[25,27] manifestations
and different of vascular
manifestations diseases
of vascular [28,29],
diseases many
[28,29],
complex
many alterations
complex occur atoccur
alterations the clinical,
at the biological, or behavioral
clinical, biological, level, which
or behavioral contribute
level, which
to the development of these foot complications [30–32]. Up to 79 risk
contribute to the development of these foot complications [30–32]. Up to 79 risk factors factors have been
retrieved and reported by Rossboth et al. [27].
have been retrieved and reported by Rossboth et al. [27].
Despite the
Despite the huge
huge progresses
progresses in in clinical
clinical and
and biomechanical
biomechanical research
research and
and relevant
relevant
technology [21,33–37], deeper knowledge, more evidence and general validity,a and
technology [21,33–37], deeper knowledge, more evidence and general validity, and larger
a
consensus
larger are needed
consensus to effectively
are needed model model
to effectively as manyasrisk
many factors as possible,
risk factors and to predict
as possible, and to
the many
predict thealterations observedobserved
many alterations in patients, both in the
in patients, bothfoot
instructure and function
the foot structure and [4–10,12].
function
[4–10,12].
Appl. Sci. 2021, 11, 11464 13 of 16

The present study focused on a small part of this complex process of correlation
and modeling. Namely, the core of the study was the hypothesis that an appropriate
stratification of patients with diabetes prior to implementing a predictive model might help
reduce the variability of the most relevant parameters and improve intra-group correlations.
In particular, it was hypothesized that subgroups defined according to type of diabetes,
presence or absence of neuropathy, and presence or absence of obesity may support a better
identification of relevant clinical, biological, structural, functional, and biomechanical
profiles and patterns.
The study was observational, with a thorough clinical, functional, and biomechanical
assessment conducted in 2016. However, a 48-month follow-up made it possible to address
two additional relevant questions, namely whether baseline profiles and patterns could at
least partially explain the onset of plantar lesions, whether two important clinical aspects—
peripheral neuropathy level at baseline and the trend of glycated hemoglobin during
follow-up—might have a concurrent role in the ulceration process.
The study showed that patients with diabetes should be stratified for both presence
of neuropathy and diabetes type. Six groups of patients were analyzed, and their profiles
and patterns were remarkably different (Table 3, Figures 2–6). Differences occurred not
only with respect to a number of largely expected variables, for example age and gait
performance between T1 and T2, but also with respect to clinical variables among the
neuropathic groups, or biomechanical variables in corresponding (i.e., non-obese) groups.
It is worth mentioning that type 2 subgroups showed peculiarities related to the presence
of neuropathy and/or obesity, but they still showed high intra-group variability of the
parameters, greater than in type 1 groups. The only exception was for the non-obese
and non-neuropathic type 2 patients. This group, however, consisted of seven patients
only, thus requiring confirmation in wider studies. While these specific profiles allow for
modeling of foot alterations within each group, the high variability definitely calls for more
studies and a more inclusive set of variables.
Some interesting results were observed for the profiles and patterns of patients who
developed lesions (PWL) during follow-up. They were quite homogeneously distributed
among the groups, showing that ulceration not only occurs in neuropathic patients. The
highest percentage (20%) of PWL was found in DNNT1, while the highest rate of lesions
(45%) was found in both DNT2 patients, obese and non-obese. The highest rate of lesions
(45%) occurred at the toes and at the dominant limb (15 dominant vs. 7 non-dominant).
PWL had very heterogeneous variations in all groups of variables. However, all of them
had an altered profile or pattern in at least one group of variables, including the passive
mobility and alignment group. In addition, HbA1c was generally out of one standard
deviation in DNT1. According to the literature, glycemic control might play a relevant role
in the prevention of diabetic foot syndrome [38,39]; thus, the present findings seem worthy
of deeper investigation. Finally, plantar pressure-related parameters (PP and PTI) were
often altered in PWL, not only at the site of lesion, and differently changed in the dominant
and non-dominant limb. All this suggests that not only plantar pressure-related variables
deserve special attention in prevention programs, but also that a thorough plantar regional
analysis should be conducted, and that feet have to be investigated separately, grouped as
dominant and non-dominant.
An exploratory additional contribution of this study came from the examination of
the 3D weight-bearing foot architecture, which provides measures of alignment obtained
by means of an innovative exploitation of the weight-bearing CT technique [11]. Three
patients with lesions (2 DNT1, 1 DNNT1) could in fact be retrieved among the subset of
DNT1 (7 patients) and DNNT1 (8 patients) who underwent analysis of the orientation
and height of the main foot segments in each anatomical plane and in 3D (84 variables in
total). The three patients showed different profiles and alterations; however, it is worth
noting that all of them showed a high percentage of variables out of the corresponding
95% confidence interval—up to 60% of the frontal plane variables for one neuropathic
patient (Figure 7) and 47% of the 3D variables for the non-neuropathic patient. While these
Appl. Sci. 2021, 11, 11464 14 of 16

findings cannot be generalized, they suggest the need for further investigation and the
inclusion of 3D architecture variables in the diabetic foot predictive models.
This study has several limitations, the most important of which are hereby briefly
commented on. The findings are not exhaustive and potentially not directly applicable to
all patients with diabetes who may develop/may have developed diabetic foot syndrome.
Patients with amputations, Charcot neuroarthropathy, severe nephropathy, retinopathy, or
vasculopathy were excluded a priori from the study due to the study timeline and resources.
Patients with type 1 and obesity, either with neuropathy or without, were not retrieved
among the Clinic Foot Center eligible patients. The contribution of gender could not
be investigated, and groups were quite heterogeneous with respect to the ratio between
women and men. In particular, the type 1 neuropathic group was mostly formed by men
while the type 1 non-neuropathic group by women. The sample size within each subgroup
may be too small to properly account for the intra-group variability of some parameters.
Special attention was paid to managing them as homogeneously as possible with respect to
foot care and prevention, also including therapeutic programs as indicated by the IWGDF
guidelines. However, it is reasonable to hypothesize that a relevant role in the onset of
plantar lesions was played by other uncontrolled factors, including patient adherence to
treatment, previous lesions or diseases, co-morbidities, and lifestyle.
Nevertheless, to our knowledge, the present work is the first to combine such a large
number of heterogeneous variables, also from a very large spectrum of instruments and
techniques.

5. Conclusions
Type of diabetes, peripheral neuropathy, and obesity contribute differently to the
development of diabetic foot syndrome. Thus, predictive modeling should consider proper
stratification of patients before modeling alterations in foot structure and function. Within
each of the identified groups, several profiles or patterns of variables—passive joint mobility
and alignment, biology and clinics, gait performance, regional peak pressure, and pressure-
time integral profiles—reveal possible roles in the development of plantar lesions, as shown
by the subset of 12 patients who developed lesions during the 48-month follow-up period.
Residual variability within each group might be further reduced by modeling additional
variables, such as those characterizing the weight-bearing foot architecture.

Author Contributions: Conceptualization, C.G., G.L., A.L., P.C., G.M. and L.B. (Lisa Berti); Formal
analysis, C.G.; Investigation, C.G., G.L., P.C., M.O., L.B. (Luca Baccolini) and L.B. (Lisa Berti);
Methodology, C.G., G.L., A.L., P.C. and L.B. (Lisa Berti); Project administration, C.G., A.L. and L.B.
(Lisa Berti); Resources, C.G., A.L., G.M. and L.B. (Lisa Berti); Software, C.G. and M.O.; Supervision,
C.G., A.L. and L.B. (Lisa Berti); Validation, C.G. and M.O.; Writing—original draft, C.G., A.L. and L.B.
(Lisa Berti); Writing—review and editing, C.G., G.L., A.L., P.C., M.O., G.M., L.B. (Luca Baccolini) and
L.B. (Lisa Berti). All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by the Italian Ministry of Health 5 × 1000 grant program.
Institutional Review Board Statement: Approval was obtained by the metropolitan ethical commit-
tee for experimental protocol 1 and by the local Ethical Committee (Prot. IOR 7685 28 July 2017) for
experimental protocol 2, and relevant informed consents were signed by participants in the study.
The study was conducted according to the guidelines of the Declaration of Helsinki.
Informed Consent Statement: Informed consent was obtained from all individuals involved in the
study.
Data Availability Statement: Data are owned by the IRCCS Istituto Ortopedico Rizzoli, the Italian
National Institute of Health, and the IRCCS-Azienda Ospedaliera di Bologna Policlinico Sant’Orsola-
Malpighi. Request to use, share or disseminate such data must be sent to alberto.leardini@ior.it.
Acknowledgments: Authors are grateful to all patients and assistants who volunteered in the study.
Conflicts of Interest: The authors declare no conflict of interest.
Appl. Sci. 2021, 11, 11464 15 of 16

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