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V. Cervelli and A. A. Pierro
With the aim of better-dening types of PRP
preparations, Ehrenfest etal. proposed a classication of platelet concentrates based on cell components and brin architecture [1]:
• Pure Platelet-Rich Plasma (PRP): prepara-
tions that do not contain leukocytes and are
characterized by a low-density brin
network.
• Leukocytes and PRP (L-PRP): preparations
that contain leukocytes and are characterized
by a low-density brin network.
• Pure Platelet-Rich Fibrin (PRF): preparations
that do not contain leukocytes and are charac-
terized by a high-density brin network.
• Leukocytes and PRF (L-PRF): preparations
that contain leukocytes and are characterized
by a high-density brin network.
A further exhaustive classication of PRP
products is the DEPA classication proposed by
Magalon etal., based on four criteria: (1) dose of
injected platelets, (2) efciency of production,
(3) purity of the PRP, and (4) activation process.
The details of the ample spectrum of PRP preparation methods and classications are beyond the
scope of this chapter; however, it is important to
acknowledge the heterogeneity in preparations
and characteristics of platelet-rich products.
Along with platelets, PRP provides a concentrate
of platelet-derived growth factors, adhesion molecules (brin, bronectin, and vitronectin), cytokines, and chemokines and, according to the
preparation method, may contain leukocytes and
red blood cells.
Platelet growth factors are either released at
the wound bed upon platelet exposure to collagen, activation, and degranulation or might be
pre-released from PRP activation processes.
Platelet-released growth factors include epidermal growth factor (EGF), platelet-derived growth
factor (PDGF), vascular endothelial growth factor (VEGF), insulin growth factor I (IGF-I),
transforming growth factors β1, β2, and β3 (TGF-
β1, TGF-β2, and TGF-β3), platelet-derived
angiogenesis factor (PDAF), platelet factor 4
(PF-4), broblast growth factor (FGF), and hepa-
Table 27.1 Platelet-released growth factors
Platelet growth
factors Biological activity
Plateletderived growth
factor (PDGF)
Vascular
endothelial
growth factor
(VEGF)
Epidermal
growth factor
(EGF)
Fibroblast
growth factor
(FGF)
Transforming
growth factor
b1 (TGF-b1)
Hepatocyte
growth factor
(HGF)
Insulin growth
factor (IGF-I)
Stimulates the proliferation of
mesenchymal cells, osteoblasts,
broblasts, smooth muscle cells;
regulates collagen metabolism;
stimulates chemotaxis of broblasts,
smooth muscle cells, macrophages,
and neutrophils
Stimulates endothelial cell
proliferation, increases vessel
permeability, and promotes
angiogenesis
Stimulates proliferation of epithelial
and mesenchymal cells, promotes
angiogenesis stimulating endothelial
chemotaxis, regulates collagenase
secretion
Stimulates proliferation of
mesenchymal cells, chondrocytes,
and osteoblasts
Stimulates proliferation of
undifferentiated mesenchymal cells,
regulates proliferation of endothelial
cells, broblasts, and osteoblasts;
regulates collagen metabolism and
growth factors signaling; stimulates
chemotaxis of endothelial cells and
angiogenesis; downregulates
proliferation of macrophages and
lymphocytes
Stimulate mitogenesis, cell motility,
and matrix invasion
Promotes broblast chemotaxis and
protein synthesis; stimulates
proliferation and differentiation of
osteoblasts
tocyte growth factor (HGF) (Table 27.1). Once
released from platelets, growth factors bind to
membrane receptors on target cells initiating
intracellular cascade, which leads to several
effects, as reported in Table27.1.
27.2 PRP Applications inChronic
Wounds
Chronic non-healing ulcers develop when the
wound fails to progress in a timely and organized manner through the healing cascade. This
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often results from a combination of systemic
and local factors, all of which may affect the
wound microenvironment. The rationale of
using PRP to promote the healing of complex
ulcers resides in the idea of optimizing the
wound microenvironment by providing a supraphysiological growth factor stimulation.
Through the activity of the wide array of biologically active mediators released, PRP seems
to promote cell recruitment and proliferation,
angiogenesis, and anti- inammatory and antibacterial activities. Although further investigation is required to clarify the exact biological
effects of single platelet-derived growth factors
released with PRP, several in vitro, animal
model, and invivo studies have been carried out
to investigate the role of PRP in the modication of the chronic wound microenvironment.
Inammation is the rst response to injury and
tissue damage and is an essential part of the
wound healing process. An optimal wound environment benets from a balanced production of
pro-inammatory and anti-inammatory cytokines. PRP favors the recruitment of innate
immune factors such as neutrophils and monocytes at the site of injury, and the release of several chemokines (CXCL4, CXCL7, and CCL5),
promoting the development of a pro- inammatory
environment [2].
Chronic wounds often show persistent inammation and overexpression of pro-inammatory
mediators. While moderate inammation is key
at the initial phases of healing as it boosts cell
recruitment, migration, and activation at wounded
site, uncontrolled persistent inammation may
hamper tissue regeneration. PRP has been shown
to have a modulatory activity on inammation,
reducing the expression of pro-inammatory
cytokines such as IL-17A and IL-1β and interfering with the NF-κB pathway via the hepatocyte
growth factor (HGF) [3, 4].
Studies investigating the role of PRP in bacterial colonization and infection of chronic wounds
have also proved PRP activity as a bacteriostatic
agent, suggesting its use as a valuable adjunct to
antibiotic therapy to limit microbial growth and
wound contamination. PRP role in limiting the
growth of common pathogens (S. aureus and S.
epidermidis) colonizing chronic wounds has
been proven; however, its effect on more complex bacterial colonies and biolms needs further
investigation [5].
After the inammatory phase, physiological
wound healing progresses through the proliferative phase, which is characterized by cell recruitment and proliferation and secretion of
extracellular matrix components and angiogenesis. PRP has been shown to stimulate this phase
of healing, via the growth factor-mediated
recruitment of cells at the wounded site. A summary of the chemotactic and mitogenic activities
of PRP-derived growth factor is provided in
Table27.1.
PRP activity of enhancing broblast proliferation and type I collagen synthesis has been
outlined [6], and in vitro studies on cultured
dermal broblasts have outlined the PRP as a
strong stimulator of matrix metalloproteinase-1
(MMP- 1). Matrix metalloproteinases degrade
extracellular matrix components and contribute
to the remodeling of the ECM, which relies on
balance of synthesis and degradation of its components. MMP-1 seems to play a fundamental
role in healing progression, being downregulated during the rst phases of the healing cascade and increasingly expressed during the
proliferation and remodeling phases [3, 7].
Through its upregulating activity on MMP-1,
PRP may enhance healing progression by promoting ECM remodeling. Among the multitude
of factors released with PRP, many have wellcharacterized pro- angiogenic activity (e.g.,
VEGF, bFGF, PDGF, EGF, HGF, IGFs, and
angiopoietin), whereas others are known to have
an inhibitory effect on angiogenesis (angiostatin, endostatins, PF4, bronectin, and vitronectin). In vitro and invivo studies have proven
PRP elicits pro-angiogenic activity, suggesting
PRP as an alternative approach for angiogenesis-related diseases and as a tissue regeneration
stimulator.
Platelet-derived TGF-1b seems to stimulate
keratinocyte proliferation by promoting epidermal remodeling and regeneration [8].
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27.3 Operative Technique
There is no specic protocol in the literature for
the preparation and application of PRP [9, 10].
Blood tests are initially carried out in order to
determine whether the patients have anemia or
similar conditions. Autologous venous blood
(20–45 mL according to wound size) is withdrawn from the patient and mixed with an anticoagulant (5 mL of 3.8% sodium citrate) using
complete aseptic technique. The blood is rst
centrifuged for 10min at 2500 rpm to separate
the blood into three layers (Fig.27.1). The upper
two layers are transferred into fresh sterile tubes
for a second centrifugation at 3500rpm for 5min.
The PRP, situated in the bottom, is aspirated and
activated by adding calcium chloride 10% in a
1:4 ratio. Each 30 cc of blood gives 3–5cc of PRP
after centrifugation (Fig. 27.2). Ulcer debridement and systemic antibiotics are offered in case
of gross infection, necrotic tissue, or positive cultures before starting treatment. The PRP may be
applied locally, as a dressing, or injected intralesionally into the edges and center of the lesions.
V. Cervelli and A. A. Pierro
Fig. 27.2 Final product obtained after the second centrifugation of the upper two-thirds of the rst
centrifugation
27.3.1 PRP Injection
First, the chronic wound must be transformed
into an acute wound. A portion of the activated
PRP is injected around the wound and under the
Fig. 27.1 Three layers of separation after blood centrifugation: red blood cells (erythrocytes) at the bottom, white
blood cells (leukocytes) and platelets in the middle, and
plasma at the top
Fig. 27.3 PRP injection in the edges of the wound
base of the wound (Fig.27.3). Petrolatum gauze
then is applied, followed by a sterile dressing.
The dressing is changed every 2days, and PRP is
applied every week until complete healing is
achieved or a maximum of 10 applications is
completed.
27.3.2 PRP Dressing
Ulcers are washed and cleaned with serum
physiologic. Wound debridement is performed
before dressing if necessary. The wound is
covered with PRP, covered with a hyaluronic
acid matrix, and fixed with cotton bands
(Figs.27.4 and 27.5). The treatment with PRP
gel is repeated once every 3 days
approximately.
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Fig. 27.4 PRP gel application over the wound
Fig. 27.5 Covering with a hyaluronic acid matrix
In a 2020 RCT reference, the two techniques
of application of PRP on ulcers were compared
and it was found that a signicantly higher proportion of ulcers healed completely after PRP
injection (24/30, 80%) than PRP application
(20/30, 66.7%) and compression therapy (14/30,
46.7%), P=0.007. The healing time in the subgroup of healed ulcers was signicantly shorter
after PRP injection as compared with PRP application and compression, P = 0.009 and 0.026,
respectively [11].
27.4 Clinical Applications ofPRP
inDiabetic, Venous,
andPressure Ulcers
Skin ulcers are open sores often accompanied by
the sloughing-off of inamed tissue. A slowhealing ulcer is typically associated with complications of poor blood circulation, such as varicose
293
veins, deep venous insufciency, and arterial and
peripheral vascular diseases. Other causes of leg
ulceration include trauma, bacterial and/or
mycotic infections, and neuropathy related to
diabetic disease. Chronic ulcers are difcult to
heal because of the diminished blood ow interfering with the healing process. Patient care is
concerned with preventing a superimposed infection in the ulcer, increasing blood ow in the
deeper veins, and decreasing pressure within the
supercial veins.
27.4.1 Diabetic Ulcer
During spontaneous wound healing, endogenous
regeneration mechanisms, and resident cell activity are triggered by the released platelet content.
Platelet-rich plasma (PRP) treatment represents
one of today’s most promising tools to promote
ulcer healing in diabetes. The diabetic condition
of poor cell numbers, reduced cell activity, or
impaired PRP efcacy may limit their usefulness.
The difculty in healing and the evolvement of
diabetic wounds to chronic ulcers are multifactorial: wound infection, deregulated inammatory
response, abnormally increased oxidative stress,
impaired angiogenesis, cell senescence, and
aberrant extracellular matrix deposition play
major roles [12]. As for diabetes, increased glucose levels elicit a specic pathogenetic response
due to molecular glycation. Glycation is responsible for vasculopathy and peripheral neuropathy,
it affects molecular function, and, in general, it
impairs the activity of the different cell types
involved in the healing process. It is widely recognized that in diabetic wound cell proliferation,
migration, differentiation, and ability to release
growth factors are impaired [13–19]. The number
of recruited circulating cells is reduced due to
decreased release of and/or response to chemotactic factors [16, 20]. Standard DFU management comprises the removal of necrotic tissue
(debridement), interventions on the infection,
and application of dressings to protect the wound
and maintain a moist environment necessary for
promoting cell activity, ofoading, and strict glycemic control [21]. Surgical intervention for correcting vascular insufciency can be considered
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V. Cervelli and A. A. Pierro
in ischemic ulcers. In the absence of an active
healing response, advanced and innovative therapies are considered. Activated platelets release
high amounts of growth factors and active molecules capable of triggering cell proliferation,
matrix remodeling, and angiogenesis to modulate
inammation at the wound site [22–26]. Plateletrich plasma (PRP) promotes recruitment at the
wound site of neutrophils and macrophages,
which stimulate vascularization and recruitment,
activation, and proliferation of mesenchymal and
epithelial stem/progenitor cells, thus enhancing
tissue repair [27].
In the last few years, the number of scientic
publications and clinical trials having PRP as a
subject has exponentially increased.
Contradictory results, however, are reported in
the scientic literature on the outcome of treatments with autologous PRP. In a 2022 randomized controlled trial by Orban YA, Soliman etal.
[28] highlighted how both methods of treatment– the traditional with weekly dressings and
the more innovative with the use of PRP– have
led to an improvement in the healing of diabetic
ulcers. There was a signicant increase, however,
in healing rate among the PRP group compared
with the conventional dressing group (31 patients
[86.11%] and 23 patients [63.89%], respectively;
P = 0.029). Additionally, the healing time was
shorter in the PRP group than in the conventional
dressing group (PRP group mean time to healing
10.90weeks ±3.40, conventional dressing group
mean time to healing 13.48 weeks ±3.37
[P= 0.01 for both]). Another major study conducted in 2021 by Hossam EM and Alserr AHK
et al. [29] highlighted how the PRP is a costbenecial novel modality of treatment that can
accelerate wound healing, decrease the rate of
local infection in DFU (10% (n=4) of the cases
in the PRP arm and 45% (n=18) of cases in conventional group; [P<0.001]), and lead to an earlier reduction TSA (PRP group ≥50% reduction
in total surface area at 2.5 weeks and conventional treatment 4.5 weeks; [P < 0.001]) compared to other conventional treatment modalities.
Other references have reported no signicant differences in the healing of diabetic ulcers using
PRP rather than conventional dressing techniques
[30, 31]. The main factor that could explain the
different treatment outcomes is the variability of
the preparations due to the lack of standardized
procedures for PRP production. Moreover,
because of the blood recovery from a single
donor, parameters such as platelet concentration,
leukocytes, red blood cells, and brin can be variable and responsible for the success or failure of
PRP treatment [32]. In general, an important
weakness of the clinical studies is the lack of
dened parameters to assess the biological quality of the PRP such as the growth factor content
and the testing of the product performance before
its clinical use.
27.4.2 Lower Extremity Venous
Chronic venous insufciency is a pathological
alteration of venous system at the lower extremities, which causes edema, chronic skin changes,
and ulceration. Improper functioning of venous
valves and venous outow impairment resulting
in long-standing venous hypertension represents
the most common cause of non-healing ulcers,
with venous leg ulcers (VLU) representing
70–90% of all chronic wounds. Venous ulcers
heal very slowly and present a high recurrence
rate among patients affected by venous insufciency. Standard of care of VLU involves wound
debridement, compressive therapy, dressings,
and antimicrobials. Alternative therapies that
have been used in the treatment of venous ulcers
include electromagnetic elds, lasers, negative
pressure therapy, and hyperbaric oxygen,
although none of these have provided an effective
strategy to enhance and accelerate healing. The
use of PRP in the management of VLU has been
investigated, and albeit in the few published studies, the limited size of sample populations and
the lack of standardization in PRP preparation
protocols have produced conicting results on
outcomes. Comparative studies on the use of PRP
in different formulations, including pure
platelet- rich plasma (PRP) and platelet-rich brin
(PRF) versus standard dressings, demonstrated
an improved reduction in ulcer area, reduction in
Ulcers
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pain, and no occurrence of major adverse events,
showing PRP as a safe and effective adjunct to
venous ulcer management [33–35]. A recent prospective study by Milek et Al. on the use of PRP
vs standard hydrocolloid dressings carried out on
100 patients showed better healing in the PRPtreated group, with improvement in ulcer area
over time. PRP was shown to promote the formation of granulation tissue at the wounded site and
reduce exudate and swelling at the edges of the
wound.
A recent meta-analysis comparing the use of
PRP versus standard conventional treatment in
patients with venous pressure ulcers conrmed a
signicant improvement in the healing rate of
VLU, while another meta-analysis failed to show
statistically signicant data in favor of PRP [36,
37]. Different platelet-derived products have
been utilized experimentally in the treatment of
VLU, including application of topical PRP gel,
injection of PRP at the wound margins, and use
of frozen autologous platelets (FAPs). Autologous
platelet gel (APG) is a viscous brin-rich gel
obtained from the combination of PRP with
thrombin and divalent calcium ions.
Despite the absence of a consensus on the use
of PRP as a standard of care in the management
of VLU, the promising outcomes outlined by
individual studies including accelerated healing
rate, improvement in quality of life, and reduction in pain warrant further investigation together
with an effort toward standardization of the PRPbased protocol.
27.4.3 Pressure Ulcers
Pressure injuries are localized damage to the skin
and/or underlying tissue induced by pressure.
These injuries often occur in patients on longterm bed rest, those with difculty moving their
lower extremities, and in patients with altered
consciousness. Pressure injuries are associated
with local tissue necrosis due to hypoxia/ischemia resulting from long-term compression [38,
39]. Routine treatments, such as antibiotic admin-
istration, dressings, and wound debridement, are
often needed; however, the treatment period is
inherently long, which inevitably increases the
risk of wound infection. Platelet-rich plasma
(PRP) gel is an emerging therapeutic option for
chronic wounds due to its simplicity in manufacturing and minimal consumables. This gel
releases high concentrations of growth factors
that stimulate cell proliferation and differentiation, seal the wound, accelerate hemostasis,
repair damaged tissue, and promote regeneration
or repair [40, 41]. However, there are currently
few clinical reports on the use of autologous PRP
gel dressings as adjuvant treatment for refractory
pressure injuries. Some of the few signicant
studies [42–45] report an improvement in pressure sores treated with the innovative PRP gel
dressing method compared to conventional dressing. One of the most recent studies shows how
the study group exhibited lower visual analog
scale (VAS) scores and pressure ulcer scale for
healing (PUSH) scores, smaller wound sizes and
depths, and shorter wound healing times than the
CG after 21days of treatment (p<0.05) [39].
27.5 PRP Combination
In consideration of the results in terms of healing times, patient satisfaction, and reduction
in the size of the lesions obtained with the
treatment of ulcers of all types with PRP, it
was decided to enhance its effects by combining it with other endogenous and/or autologous products. We report a study conducted on
100 patients suffering from pressure ulcers
treated with standard care, PRP dressing, or
PRP dressing + hyaluronic acid. The objective
of this study was to evaluate the clinical efficacy (as measured by ulcer area) and safety (as
measured by signs of infection) of PRP and
PRP plus HA in the treatment of pressure
ulcers (PUs). At 36days, a significant reduction in ulcer area (p≤0.001) was observed in
all treatment groups, with a mean reduction of
more than 48.0% versus baseline. The greatest
mean reduction (80.4% vs. baseline) was
obtained with the PRP plus HA regimen.
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Complete wound healing was observed in
32.0% of PUs treated with two doses of PRP
(p≤0.002) and in 37.5% of those treated with
two doses of PRP plus HA (p≤0.004) [46].
Another important and innovative study on
the modalities of PRP enhancement in ulcers,
evidence of the literature, demonstrates how
the combined use of enhanced stromal vascular fraction (e-SVF) and fat grafting with
platelet-rich plasma (PRP) significantly
improves the healing of patients post-traumatic extremity ulcers. The authors showed
that wounds treated with e-SVF healed better
than those treated with hyaluronic acid. In
fact, after 9.7 weeks, patients treated with
e-SVF underwent 97.9% ± 1.5% reepithelialization compared to 87.8%±4.4% of
the first control group (only hyaluronic acid;
pb0.05). Patients treated with PRP and fat
grafting also showed an improvement in reepithelialization; in fact, after 9.7weeks, they
underwent a 97.8%±1.5% re-epithelialization
compared to 89.1%±3.8% of the second control group (only PRP; pb0.05) [47].
27.6 Conclusions
Although several studies have demonstrated the
efcacy of PRP in the treatment of chronic
wounds, further research is necessary to better
understand its mode of action. In particular, it
would be crucial to determine the ideal PRP concentration in order to obtain a well-standardized
protocol of use. Unfortunately, there is still not a
routine use of PRP for chronic wound care in
Italy due in part to a poor organization of health
facilities and legislative issues. This often results
in the necessity for an operatory room to perform
this non-invasive procedure, which wastes
resources and increases costs for both hospitals
and the sanitary system. With the spread of regenerative medicine, we believe there will be a simplication in the execution of this procedure that
will benet both patients and the healthcare
system.
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Minimal Invasive Modality (MIMo)
https://t.me/medicina_free
inBurn Wound Care
AlessioDe Cosmo, GiuseppeDi Gioia,
GiulioMaggio, andGiuseppeGiudice
28
28.1 Introduction
Burns are common traumatic injuries caused by
heat, cold, or chemicals that can lead to supercial to full-thickness skin and soft tissue damage.
Although in most studies there is evidence of a
reduction in incidence and mortality associated
with burns, these injuries represent the fourth
most frequent cause of trauma worldwide and are
still cause of morbidity and mortality, prolonged
hospitalization, disability, and retracting scars
that affect the quality of a patient’s life.
Care of the patient with burns extends along a
lengthy continuum, spanning months to years.
Patients often require prolonged initial acute hospitalizations, extensive rehabilitation, scar contracture releases, and reconstructive and cosmetic
procedures.
The conventional treatment of the burn patient
is based on surgical escharotomy, constant medications, and nal coverage with partial-thickness
skin grafts (SOC: standard of care). In the recent
decades, several studies focused on the investigation of an effective debridement technique capable of removing all necrotic tissue while
A. De Cosmo · G. Di Gioia · G. Maggio
G. Giudice (*)
Unit of Plastic and Reconstructive Surgery,
Department of Precision and Regenerative Medicine
and Jonic Area, Bari, Italy
e-mail: giuseppe.giudice@uniba.it
preserving the vital dermis, in order to improve
the patient’s outcome and the quality of the subsequential scar [1].
28.2 Burns Standard ofCare
(SOC)
Initial burn care originates at the accident scene
with emergency medical services performing an
initial survey, assessment, and the beginning of
the resuscitative efforts. One decision made by
emergency personnel is to determine whether an
individual requires care at a regional burn center
[2].
The burn wound is extensively cleaned with
mild soap and water with the goal of removing all
nonviable tissue. Once the wound is clean, topical antibiotics are applied to all supercial burns
and in some cases to deep burn wounds, particularly pending timing of surgery. Initial dressings
should include non-adherent mesh gauze. Topical
agents and medication regimes will be adjusted
frequently throughout hospitalization depending
on the status of the wounds.
Burn wounds can often progress or worsen
with time as the retained heat from the injury
continues to damage tissue. Therefore, it is necessary to continue to monitor the wound for conversion of the burn to a deeper level. It is not
uncommon for second-degree burns to convert to
third degree, for example.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
M. Maruccia et al. (eds.), Pearls and Pitfalls in Skin Ulcer Management,
https://doi.org/10.1007/978-3-031-45453-0_28
299
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