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13 Biomechanics oftheDiabetic Foot: TheRoad toFoot Ulceration
https://t.me/med1917
Fig. 13.9 Diabetic foot with
and without ulcers history and
spatiotemporal changes
during GAIT.Note: foot with
ulcer history, sustain reduced
ground reaction forces
vertically and anteroposterior
(fz–fy), due to conservative
foot rollover and increased
mediolateral GRFx, due to
imbalances from lost
proprioception and
kinesthesia
245
Development ofDiabetic Foot Ulceration
DuetoPhysiological, Habitual,
andBiomechanical Alterations
The breakdown of the diabetic foot has traditionally been
considered to result from peripheral neuropathy and peripheral vascular disease. As discussed before, other contributory
factors such as limited joint nobility, high plantar pressures,
deformities, autonomic neuropathy, and psychological factors are implicated.
Peripheral vascular disease itself, even severe, does not
cause foot ulceration. Minor injuries and/or infections will
increase the demand for blood supply beyond the circulatory
capacity. In the presence of peripheral vascular disease, the
failure of the circulating blood rising in the region causes ischemia and hypoxia, resulting in tissue destruction and development of an ischemic ulcer or gangrene [106] (Chart 13.1).
Many studies have conrmed the role of diabetic neuropathy in the etiopathogenesis of foot ulceration. Crosssectional data conrmed that neuropathy is present in up to
90% of foot ulcers alone or in combination with peripheral
vascular disease [107]. The EURODIALE study included
1229 consecutive persons presenting with a new foot ulcer in
ten European countries. At baseline, peripheral vascular disease was diagnosed in 49% and diabetic neuropathy in 86%
of the participants [108]. Prospective data demonstrated that
neuropathy assessed by vibration perception over 25 Volts
was associated with a seven-fold annual increase in the risk
of ulceration in a 3-year follow-up period [109, 110]. Another
large prospective study described that beyond other factors
including previous ulceration, foot deformities, reduced
pedal pulses, neurological modalities like insensitivity to the
10g monolament, and a neuropathy disability score ≥6
were independently associated with almost two times higher
risk of foot ulceration over a 2-year period [111]. The above
data clearly suggest that neuropathy is a strong risk factor for
foot ulceration. Yet, the neuropathic foot does not ulcerate
spontaneously and it is the combination with other factors
that lead to skin breakdown. The pathway neuropathy contributes to foot ulceration is depicted in Chart 13.1.
Reiber etal. used the Rothman model for causation and
applied this to ulceration [112]. The model is based on the
concept that a component cause (neuropathy or peripheral
vascular disease) is not sufcient itself to lead to ulceration,
but when component causes act together, they may result in
a sufcient cause which eventually leads to ulceration. They
showed that the commonest triad of component causes present in 63% of ulcers was neuropathy, foot deformity, and
trauma [112]. Trauma could be intrinsic, such as repetitive
stress from high pressure and/or callus, or extrinsic such as
from ill-tting footwear rubbing on the skin or an object
inside the shoe (e.g., drawing pin and pebble). Examples of
two-component pathways to ulceration are neuropathy and
mechanical trauma caused by ill-tting footwear or callus or
deformities; neuropathy and thermal injury caused by hot
water or heating devices; and neuropathy and chemical
injury caused by “corn-cures” [111]. As trauma plays a key
role in the pathogenesis of ulceration, it is important to try to
minimize the risk of trauma in patients with loss of protective sensation implementing preventative care such as the
provision of appropriate foot care, education, and referral for
podiatry treatment.
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P. V. Tsaklis and N. Tentolouris
Diabetes mellitus
somatic sensory
neuropathy
¯perception of pain,
temperature and
proprioception
Chart. 13.1 The pathway to foot ulceration. (Modied from reference 100, with permission)
somatic motor
neuropathy
smallmuscle wasting
foot deformities
plantar pressures
foot at risk
foot ulcer
autonomic neuropathy
¯ sweating
dry skin
callus formation
trauma
peripheral arterial disease
altered blood flow
distended foot veins
warm feet
Most ulcers in diabetic patients with neuropathy occur at
sites of high plantar pressures or stress [9, 11, 13]. High pres-
sures are not usually found in healthy people and would
result in pain during ambulation for an individual with adequate sensation. For example, patients with gross foot deformities from rheumatoid arthritis do not develop ulcers
because they can feel the pain and adjust their gait to avoid
bearing load on a painful area [75]. The repetitive application of high pressures and stress to the same area, usually
overlying bony prominences, in the presence of neuropathy
causes tissue damage that begins close to the bone [9, 91].
Callus develops as a result of increased pressure at the surface in order to protect the skin from further damage; in the
presence of neuropathy, it is not perceived by the patient who
continues his activity and if callus formation becomes excessive, it will contribute to higher pressure [93]. Foot deformities, reduced LJM, and fat pad are usually responsible for the
excessive pressures. The tips of the clawed toes can themselves be locations of ulcers due to concentrated pressure
[113, 114]. In addition, healing of plantar ulcers is prevented
as long as patients keep walking on their foot wounds, thus
highlighting the key issue of mechanical off-loading. Thus,
excessive and/or repetitive pressures appear to be the main
causative factor for development of skin breakdown.
There are three main mechanisms that account for the
occurrence of these pressures: (1) increased duration of pressures; (2) increased magnitude of pressures, or (3) increased
number of pressures [93]. The rst mechanism includes relatively low pressures applied for a long period of time causing
ischemia. Prolonged ischemia leads to cell death and wound
formation, as has been demonstrated in a classic experiment.
It should be noted that some regions of the plantar tissue
become ischemic during standing and walking. Plantar pressure in the forefoot during walking is at least 30 times higher
than the systolic blood pressure in the arterial bend and even
higher at the arterioles, implying that blood ow will be
occluded during gait cycle [13, 115]. Recovery from this
transient ischemia can be affected by changes in microcirculation caused in the early course of diabetes, nutritional status, and arterial disease.
13 Biomechanics oftheDiabetic Foot: TheRoad toFoot Ulceration
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247
High pressures took a relatively short time to cause ulceration whereas low pressures took a relatively long time.
Thus, ulceration can develop at very low pressures, but may
take a few days to occur. This type of offending pressure and
resulting ulcers can occur with ill-tting footwear, improperly tted orthotics, or prolonged resting of a heel on a bed or
footrest [73]. The second mechanism of tissue injury includes
high pressures acting for a short-time period. This injury
only happens if a large force is applied to a relatively small
area of skin; this happens, for example, if a person steps on a
nail. Alternatively, a “foot slap” may also conform to this
mechanism. A “foot slap” indicates a reduced deceleration of
the forefoot after heel strike caused by weak dorsiexion
muscles [113]. It is therefore suggested that control of the
velocity of the forefoot descending after heel strike by using
ankle-foot orthosis could possibly help in prevention of diabetic foot ulcers [113]. The third mechanism of injury comes
from repetitions of pressure, which would lead to an equivalent syndrome of mechanical fatigue [93]. Mechanical
fatigue is dened as failure of a structure or biological tissue
at a submaximal level to maintain integrity resulting from
repeated bouts of loading. This type of injury seems to occur
in the insensitive skin and subcutaneous tissue of the neuropathic foot [115].
Thus, not only the magnitude of the plantar pressure is
important in causing foot ulceration but also several other
factors such as the rate of increase of pressure, duration of
high pressure, and the frequency of applied pressure to the
skin should be taken into account. In addition, although foot
pressures may be high during a barefoot pressure assessment, it is important to keep in mind that it is the combination of footwear, life style factors, tissue characteristics, foot
pressures, and level of physical activity, which contribute to
the development of foot ulceration. The effect of physical
activity on development of foot ulceration is an area which
deserves further exploration.
Another important issue in foot injuries is footwear.
While appropriate footwear can be of great benet in preventing ulcers, incorrect footwear can actually cause ulceration [9]. It is not uncommon for the patients with loss of
protective sensation to wear a pair of shoes three sizes too
small because a very tight t stimulates the pressure nerve
endings and this is interpreted as a normal t [9, 113]. The
EURODIALE study described that the majority of ulcers
(52%) were located on the non-plantar surface of the foot
and the most frequent ulcer site was the dorsal or interdigital
area of the toes (32%), while the classic plantar forefoot or
midfoot ulcer was present in 22% of the patients [101]. This
nding implies that a large number of ulcers develops as a
result of poor footwear and emphasizes the need for footwear education for the prevention of foot ulcers.
Kinetic Control andDiabetic Peripheral
Neuropathic Patient's Balance andMobility
The musculoskeletal kinetic control is the process through
which someone is able to fulll the locomotor requirements
in any given task or day live activities, like gait and balance,
adapting and synchronizing his neuro-musculo-skeletal system components. To manage activities of daily life, the
Central Nervous System coordinates postural components
which stabilize the body and the prime mover components
which relate to the particular motor task on basis of an internal representation of body posture, including a model of
body geometry, body kinetics, and body orientation with
respect to gravity. Thus, to function in daily life, an individual must be able to maintain and adopt various postures,
react to external disturbances, and use automatic postural
responses that precede voluntary movements.
For the diabetic neuropathic person, impaired balance is
one of the most common risk factors associated with falls
[38]. Diabetic neuropathy may compromise postural stability since the integrity of the Kinetic Control and its adjusted
proprioceptive system is a critical factor for postural stability. The balance ability, is a complex outcome that requires
the integration of multiple sensorimotor and cognitive processes [99]. DPN has long been considered the most dominant mediator between diabetes and falls because of reduction
in lower-limb somatosensation, thus, reduces the ability to
detect changes in balance and make appropriate adjustments
to avoid a fall [39, 121]. Furthermore, age-related deterioration in those systems can disrupt the ability to maintain balance [38, 99].
The kinetic control and balance are based on three sensory
systems (somatosensory, visual, and vestibular), which contribute the sensory information required for balance control.
Peripheral neuropathy affects the sensory, motor, and autonomic components of the nervous system and presents as a loss
of sensation, intrinsic foot muscle atrophy, and foot skin anhydrosis [39]. That's a long term result of the affected microcirculation associated with poor glycemic control in type 2 diabetes,
which eventually compromises those systems.
The somatosensory system provides information about
the position and motion of body’s segments in relation to
each other and the support surface by using proprioceptive
(joint position/kinesthesia) and cutaneous (touch and vibration sensitivity) inputs. Long-term hyperglycemia can lead
to a progressive deterioration of sensory nerve bers in the
somatosensory system and eventually to DPN.Muscle spindles which provide rapid information about changes in muscle length and the Golgi organs of tendons which sense
changes in muscle tension are affected and the cutaneous
mechanoreceptors which provide information about vibra-
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P. V. Tsaklis and N. Tentolouris
Fig 13.10 “Good” static balance prerequisites: minimum COP sway
velocity mm/sec and COP sway area mm2 and even body weight distribution %; case: individual with DPN.Assessment of static balance, during
tion and pressure sensations, as well [38]. Thus, the greater
motor error at the joints (higher g forces) leads to motor control decits.
The visual system provides information about the environment and body orientation. Long-term hyperglycemia
affects the circulatory system of the retina and can lead to
diabetic retinopathy. Older adults with type 2 diabetes and
reduced contrast sensitivity have been reported to be 1.41
times more likely to fall as compared to older adults without
type 2 diabetes [38].
The vestibular system provides information about head
position (thus, adjusting body posture), spatial orientation,
and spatio/temporal input, especially the sense of velocity/
acceleration. Long-term hyperglycemia causes inammation
and reduced sensitivity of the highly active metabolic vasculature in the inner ear. Vestibular dysfunction has been
reported to be 2.3 times more likely in those with diabetes
than in those without diabetes [114]. The vestibular appara-
open and closed eyes quite bipedal stance. Loss of sensation—proprioception and kinesthesia, lead to major decits in COP sway velocity and
COP sway area and eventually, limited motor control
tus in the inner ear (labyrinth) and nerve synapses is highly
vascular and the poor supply of oxygen decreases the autonomic and somatic reexes.
Eventually, deterioration of one or more of those sensory
systems reduces the peripheral information and the ability of
the central nervous system to compensate and organize the
kinetic strategy of the individual and that affects balance and
increases fall risk. Therefore, it is critical to assess not only
somatosensory functions related to DPN but also visual and
vestibular functions, which can contribute to impaired balance and falls [39].
The effect on postural stability* during stance and gait is
very detrimental, with highly negative inuence on mobility
and thus, quality of life. The evaluation of the static and
dynamic balance is usually based on the interpretation of
center-of-pressure (COP) measures using a dynamometric
platform (force-plates, pedobarographs etc.) [114] (Figs.13.9
and 13.10).
13 Biomechanics oftheDiabetic Foot: TheRoad toFoot Ulceration
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249
Fig 13.11 “Good” dynamic balance prerequisites: Case: Sit to stand; maximum COP antero-posterior, latero-lateral, or diagonal displacements
(amplitude in mm) and minimized corresponding times (sec) for both the active (a–e) and recovery (e and f) phases
Many studies have reported that DPN patients are less
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Cell Therapies: New Frontier
https://t.me/med1917
fortheManagement ofDiabetic Foot
Ulceration
SashaShenk, RamoneBrown, OlgaKashpur, AviSmith,
RyanImbriaco, BradfordGreaves, BehzadGerami-Naini,
andJonathanA.Garlick
14
Abstract
While stem cells hold great potential to improve existing
therapies for diabetic foot ulcers (DFUs), their promise
has not been fully exploited. There is a critical need to
further develop existing sources of adult stem cells and to
test novel sources of induced pluripotent stem cells
(iPSCs) to improve impaired wound repair when delivered to DFUs. This chapter summarizes the capacity of
multiple adult stem cell sources, including bone marrowderived mesenchymal stem cells, hematopoietic stem
cells, endothelial progenitor cells, bone marrow and
peripheral blood mononuclear cells, and adipose stem
cells, to improve DFU healing outcomes in pre-clinical
animal models and human clinical trials. We also review
more recently developed technologies, such as iPSCderived cell sources, CRISPR gene editing, and 3D human
skin equivalent tissue models to generate diverse cell
types needed for DFU healing and to streamline their preclinical testing. By further understanding how stem cells
and related new technologies can best stimulate tissue
regeneration, we will be able to overcome existing barriers to improve DFU therapies.
S. Shenk · R. Brown · O. Kashpur · R. Imbriaco · B. Greaves
B. Gerami-Naini
Department of Diagnostic Sciences, School of Dental Medicine,
Tufts University, Boston, MA, USA
e-mail: sasha.shenk@tufts.edu; Ramone.Brown@icahn.mssm.edu
olga.kashpur@tufts.edu; ryan.imbriaco@tufts.edu;
bradford.greaves@tufts.edu
A. Smith
Olympus Inc, Waltham, MA, USA
e-mail: avi.smith@tufts.edu
J. A. Garlick (*)
Department of Diagnostic Sciences, School of Dental Medicine,
Tufts University, Boston, MA, USA
School of Medicine, Tufts University, Boston, MA, USA
Graduate School of Biomedical Sciences, Tufts University,
Boston, MA, USA
e-mail: Jonathan.Garlick@tufts.edu
Abbreviations
ASCs Adipose-derived stem cells
BM-MSCs Bone marrow-derived mesenchymal stem
cells
BM-MNCs Bone marrow-derived mononuclear cells
DFU Diabetic foot ulcers
EPCs Endothelial progenitor cells
ECM Extracellular matrix
HSCs Hematopoietic stem cells
HSEs Human skin equivalents
iPSCs Induced pluripotent stem cells
PBMCs Peripheral blood mononuclear cells
UCB Umbilical cord blood
Introduction
The cellular complexity of diabetic foot ulcers (DFUs) presents both opportunities and challenges for the development
of new cell therapies designed to stimulate the healing of
chronic wounds. Temporally and spatially coordinated interactions between multiple cell types and their products, such
as extracellular matrix (ECM) proteins and soluble cytokines
and chemokines, are critical for wound closure [1–4].
Impaired mechanisms of wound repair in non-healing DFUs
are manifested by aberrant neovascularization, alterations in
deposition, organization and remodeling of ECM, altered
growth factor-mediated cellular crosstalk, and impaired reepithelialization [5–13]. Cell therapy for DFUs must overcome these compromised cellular interactions that limit
activation of a regenerative connective tissue stroma.
Stem cell therapy is emerging as a promising treatment
modality aimed at improving processes underlying the
pathophysiology of DFUs. Stem cells have been shown to
“home” to wounds where they are mobilized to secrete chemokines and growth factors that promote angiogenesis and
ECM remodeling, thus contributing to a local environment
conducive to wound healing [14–17]. A key question facing
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. Veves et al. (eds.), The Diabetic Foot, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-55715-6_14
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S. Shenk et al.
the success of future cell therapies is whether the delivery of
these cells directly to the DFU tissue environment has the
potential to activate the repair processes that are decient in
these non-healing ulcers. In light of the multiple cellular
defects that contribute to DFUs, it is essential to identify and
study additional stem cell types that can restore a range of
normal cellular functions to the wound microenvironment. It
is possible that multiple cell types will need to be delivered
in the hope that they will persist and function at the wound
site to activate and sustain wound healing in ways that
advance the treatment of DFUs.
Stem cells used to promote healing in DFUs can be categorized into allogeneic and autologous cell sources, based on
their relation to the donor from whom they are derived.
Allogeneic stem cells are dened as cells that are derived
from the same species as the recipient but are neither genetically matched nor immunologically compatible with the subject receiving them. Allogeneic cells have been shown to
persist for a limited amount of time during which they may
recruit other cells that activate biological processes neces-
sary for wound repair [18–20]. In contrast, autologous stem
cells are cells collected from and then used in the same individual. Autologous cells have been shown to survive at the
site of delivery and to activate wound repair processes. These
cell therapies are often evaluated in xenogeneic animal models, in which these human cells are tested for treatment in
other species that have relevance to DFU wound repair.
Stem Cells andDFU Therapy
Stem cells that have been tested and implemented as clinical
therapies include bone marrow-derived mesenchymal stem
cells (BM-MSCs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs), bone marrow-derived mononuclear cells (BM-MNCs) and peripheral blood mononuclear
cells (PBMCs), endothelial progenitor cells (EPCs), and
adipose-derived stem cells (ASCs). This chapter will summarize progress in the use of these sources of stem cells to
heal and repair DFUs (Fig.14.1). We will review the animal
Fig. 14.1 Potency, source, and functions of stem cells used to treat
DFUs. Multipotent and unipotent cells are derived from various tissues
and classied based on their capacity to differentiate into functional cell
types. Pluripotent stem cells can be differentiated into nearly all cell
types and can be modied using CRISPR gene editing. These cell types
can be screened and tested in 3D, in vitro human tissue models and
subsequently in animal models before being tested in human clinical
trials. This will determine the clinical benet through wound repair processes such as angiogenesis, extracellular matrix production, growth
factor secretion, and re-epithelialization
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