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76 V. Viswanathan and R. Mirshad
Viswanathan V, Nachimuthu S. Major lower-limb amputation during the COVID pandemic in
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Biologic Transducers in Wound
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Healing
Biao Cheng and Xiaobing Fu
Abstract
Chronic wound management includes many ways: physical (light, electricity,
oxygen, etc.), drug and dressing. With the rapid development of biom edical field
in recent years, the application of recombinant growth factors or/cytokines, cell
therapy has opened up a new way in the treatment of chronic wound and has
shown great prospects. There has been a lot of evidence such as RCTs showing
that these treatments are safe and promising. There are still many problems to be
discussed in the application process. This includes the way of drug delivery of
growth factors, the best combination therapy. Organic combination of cellular
biological scaffold, seed cells (like stem cells) and growth factor/cytokines will
constitute the ideal regenerative treatment technology for chronic wound
healing.
Keywords
Chronic wound Growth factor Cell therapy
Abbreviations
ASCT Autologous stem cell therapy
DFU Diabetic foot ulcer
EPT Enriched platelet treatment
EGF Epidermal growth factor
ECM Extracellular matrix
FGF Fibroblast growth factor
GFs Growth factors
B. Cheng X. Fu (&)
Beijing, China
e-mail: fuxiaobing@vip.sina.com
R. Mani (ed.), Chronic Wound Management,
https://doi.org/10.1007/978-3-031-26110-7_5
77© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
78 B. Cheng and X. Fu
GRADE Grading of Recommendations Assessment Development and
Evaluation
GM-CSF Granulocyte-macrophage colony-stimulating factor
PRP Platelet-rich plasma
PDGF Platelet-derived growth factor
RCTs Randomized controlled trials
VLUs Venous leg ulcers
Introduction
The proces
inflammation,
s of wound healing generally consists of four stages, blood clotting,
proliferation and tissue remodeling. Wound healing is a tightly
regulated physiological process. The biological process of dynamic and complex is
involving in multiple factors such as kinds of repairing cells, proteins and a series of
factors, such as chemokines, cytokines and growth factors (GFs), which play
essential roles. The cytokines/growth factors not only participate in inflammation
and initiate immune regulation, but also prom ote the proliferation, differentiation
and migration, induce apoptosis of repairing cells, including fibroblasts, vascular
endothelial cells, and keratinocytes, etc., regulate the composition of the extracellular matrix (ECM), the synthesis and degradation of proteins, as well as perfrom
the remodeling of new formation tissues. Once the connection of the processes
found no match, healing should stasis at a certain stage. The number and function
of cytokines/growth factors and its receptors play important roles in the whole
process. Its pathophysiological basis might be decreased activity and/or relative or
absolute absence of cytokines/growth factors and their receptors is non-healing
wounds (Broughton et al. 2006). It becomes a theoretical foundation for topical
Fig. 1 Enriched platelet, recombinant cytokines/GFs or (stem) cells to promote skin and soft
tissue healing
Biologic Transducers in Wound Healing 79
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using autologous and recombinant cytokines/GFs or (stem) cells to promote skin
and soft tissue healing in various kinds of wounds, especially chronic ulcer (Fig. 1).
With the furt her increase global population aging, health problems are becoming
more and more worrying, among
which chronic wounds have become a major
problem of the healthcare system. The treatments for these refractory wounds
include surgical and non-surgical methods. Nevertheless, these hard-to-heal wounds
often represent a difficult challenge with the currently normal treatment. As a
non-surgical, biotherapy technique, the application of various active factors,
including cytokines, growth factors (GFs) is the promising methods to promote
directly wound healing or provide healthy wound beds for surgical or other treatments. According to the growth factor preparation method, it might blood-derived
platelet releasing, or bioengineering technology production. platelets could
release a composite of multiple chemokines, cytokines, and growth factors, etc.
Platelet concentrates, such as platelet-rich plasma (PRP), platelet-rich fibrin (PRF),
and/or platelet lysate (PL), could enhance healing and stimulate the regeneration
of skin ulcers (Oneto and Etulain 2021). Recombinant GFs (rGFs) have been used
on chronic wound in many countries of all over the world as early as many years
ago. So far, have still not found obvious toxicity or severe adverse reactions in the
treatment wounds with rGFs.
In addition cellular therapy, especially stem cell, could accelerated wounds
closure, which is relationship with its autocrine and paracrine molecule signaling
mechanisms contribute to increasing epithelialization, granul ation tissue formation
and angiogenesis of chronic wounds (Hocking and Gibran 2010).
Effectiveness of Enriched Platelet for Skin Chronic Wounds
After tissue injury, there is an immediately hemostatic response that activates platelets, then it release chemokines, cytokines, growth factors (GFs), and
many molecules enabling the recruitment of the repaired cells, such as inflammatory cells, fibroblasts, etc. Following on, these platelet-derived factors are involved
in the fundamental stages of wound healing. The platelet-derived factors (for
example cytokines, growth factors) have been extensively used for tissue repair
and regeneration in clinical (Serra et al. 2013). The reasons for the widespread
using platelet derivatives in the process of healing is due to the abundance of
cytokines/GFs and other signaling molecules (for example fibrin, etc.) in platelets.
Platelet-derived factors have its specific cellular targets, once they are released, bind
to receptors thus transmit the signal from the plasma membrane to the nucleus and
signaling cascades finally activating the expression of target genes, then promote
cell migration, proliferation, differentiation, and induce cell apoptosis, accelerate
the healing process (Zhang et al. 2019).
Enriched platelet treatment (EPT) is considered to be an advanced wound
therapy, especially for chronic ulcers. For nearly 30 years, platelet-derived products
have been used to stimulating chronic wound healing (Amable et al. 2013).
80 B. Cheng and X. Fu
In 2011, a systematic revie w and meta-analysis showed there were statistically
significant differences for complete wound healing treatment with PRP (platelet
lysates, platelet freezing, etc.) compared to saline gel or no topi cal treatment (Carter
et al. 2011).T
two RCT studies evaluated time to heal and both showed sig-
hese
nificant improvements wounds (chronic wound, diabetic ulcer, pressure sore, etc.) in
PRP treated subjects versus the control groups (saline gel or no topical treatment).
Two RCT studies showed statistically significant differences in wound area reduction compared to saline gauze or no topical treatment controls (Driver et al. 2006). It
should be noted that the 2 studies that did not detect significance at weeks 5. But at
week 8 there were statistically significant wound area reductions compared to saline
gauze or no topical treatment suggesting that a longer study period may have
detected complete healing. Likewise, a non-RCT, comparative study revealed significant area and depth reductions with 2.5- to 3.5-fold decrease in time to reach 50%
compared to pretreatment moist wound care controls. Adverse events were consistently lower for PRP groups than for controls of saline gauze, saline gel or no topical
treatment (Anitua et al. 200 8 ; Saldalamacchia et al. 2004). A historical cohort study
revealed that platelet rich plasma subjects required significantly fewer days to
complete healing compared to hyaluronic acid dressed wounds (Mazzucco et al.
2004). One systematic review concluded that the percentage of total healing in
PRP-treated skin soft tissue ulcers consistently increased compared to the control
(Martínez-Zapata et al. 2009). Another meta-analysis of chronic wound studies
confirmed the use of PRP treatment favored complete healing compared to control
care. Other systematic reviews on PRP therapy acquired the same conclusions
(Villela and Santos 2009). In 2019, a systematic review concluded that based on the
meta-analysis and scientific evidence regarding consistent favorable outcomes, EPT
is a valuable and safe therapy method for chronic non-healing ulcers. And the means
was simple to prepare and has remarkable effects. In future, some high-quality
prospective studies are necessary to verify these conclusions (Xia et al. 2019).
That same year, another meta-analysis also showed that platelet-rich plasma
could be considered a candidate means for nonhealing of diabetic foot ulcers
(Pino-Sedeno et al. 2019). Another thing to note autologous platelet-rich plasma
(PRP) is safe due to its autologous nature, and its preparation is from patient's own
venous blood. Although there were a few reports about allogeneic EPT has been
successfully used in chronic wounds (Liao et al. 2020).
In 2021, Fang et al. systematically evaluated the clinical effectiveness of
platelet-rich plasma for treating lower limb venous ulcers by meta-analysis. A total
of 294 patients with lower extremity venous ulcers were included in six publications, including
148 patients in the experimental group treated with PRP versus 146
patients in the control group treated with conventional therapy. There was a statistically significant difference in the area of an ellipse at the end of treatment (CM
between the experimental group and the control group, with a mean difference of
−1.19 (95% CI −1.80 to −0.58, P = 0.0001; 6 studies, 294 participants moderate
quality of evidence). The difference between the healing rate of the experimental
group and the control group was statistically significant, with a risk ratio (RR) of
5.73 (95% CI 3.29–9.99, P < 0.00001; 5 studies, 248 participants moderate quality
2
)
Biologic Transducers in Wound Healing 81
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of evidence). There may be publication bias for both area of an ellipse at the end of
treatment and healing rate. This comprehensive meta-analysis of available evidence
suggests that the application of PRP for lower extremity venous ulcers wound
accelerate the ulcers healing process and improved wound healing quality (Fang
et al. 2021).
The next year, Qu and his colleagues found that PRP may be a beneficial means
of treating chronic skin ulcers, significantly improved the rate of complete healing
of chronic cutane ous ulcers, and that autologous PRP (APRP) may be much safer
than homologous product. Finally, the authors
suggest that more high-quality
randomized controlled trials were needed to refute or confirm the current conclusions (Qu et al. 2022). In the same year, Yammine systematic reviewed the
effectiveness of PRP versus the standard of care commonly used to treat venous leg
ulcers (VLUs). This meta-analysis further demonstrated significant advantageous effects of PRP versus standard of care on healing rate, reducing ulcers surface of VLUs. At the same time, infection and other complications were similar to
standard of care. Therefore, the data would support the use of PRP as a safe and
effective means for VLUs (Yammine et al. 2022).
Platelets are small discoid blood cells, they have a trilaminar cell membrane with
protein receptors surface overlying and are partially interspersed with a penetrating
bilayer of phospholipids and cholesterol. Platelets lack nuclei but contain organelles
and structures such as mitochondria, microtubules, peroxisomes, lysosomes, and
granules (a-, dense-) (Akingboye et al. 2010). Therefore, concentrated platelets, as
autologous cellular therapies technology, were utilized in a variety of regenerative
medicine treatment plans (Everts et al. 2020). The cellular therapy of concentrate
platelets also has shown promise more and more in the management of diabetic foot
ulcer in many preclinical experiments and clinical research. A total of 6 randomized
controlled clinical trials involving 241 individuals were included in a meta-analysis.
The scholars found cellular therapy of concentrated platelets could accelerate the
rate of diabetic foot ulcer healing an d showed higher ABI, TcPO2, and lower scale
of pain and amputation risk. And it seemed to be safe, with no serious complications and low risk of short-term slight complications (Zhang et al. 2017a).
About other cellular therapy (for example stem cells) of chronic wounds would
be introduced in the following section.
Effectiveness of Topical Recombinant Growth
Factors/Cytokines for Chronic Skin Wounds
ing wound healing is helpful to restore the vital barrier function of skin and
Promot
soft tissue defects. In cooperation with clinicians and industrial partners novel
biotherapeutic concepts including the topical application of recombinant
cytokines/growth factors have been developed. Cytokines and growth factors that
have been tested in clinical studies such as granulocyte–macrophage
colony-stimulating factor (GM-CSF), platelet-derived growth factor (PDGF) and
82 B. Cheng and X. Fu
Fig. 2 Topical application of recombinant cytokines/growth factors accelerating chronic wound
healing
fibroblast growth factor (FGF), and epidermal growth factor (EGF). These studies
showed that an important aspect of the growth factor accelerating wound healing
paradigm is the sufficient effective delivery of these exogenous GFs or cytokines to
the wound site (Fig. 2).
At present, several approved medications including recombinant growth factors
are available as preparations for external use in the form of solutions, powder,
ointments, creams, and gels. Up to now, bioengineered product s of growth factors
include epidermal growth factor
(EGF), fibroblast growth factor (FGF), and etc.
Industrial products of cytokines are represented by granulocyte–macrophage colony stimulating factor (GM-CSF). These products have b een used in wound healing
(contain chronic ulcers) over decades. The scholars evaluated the effectiveness and
safety of GM-CSF to treat skin and soft tissue wounds. They searched
PubMed/Medline (1980–2020), Cochrane Library (1980–2020),
Cochrane CENTRAL (from establishment to 2020), ClinicalTrials.gov (from
establishment to 2020), Chinese Journal Full-text Database (CNKI, 1994–2020),
China Biology Medicine disc (CBM, 1978–2019), Chinese Scientific Journal
Database (VIP, 1989–2020) and Wanfang Database (WFDATA, 1980–2019).
Randomized controlled trials (RCTs), quasi-RCTs and contr olled clinical trials
treating patients with acute skin wounds from various causes and with those
available growth factors were included. Results: A total of 7573 papers were
identified through databa se searching; 229 papers including 281 studies were kept
after final screening. Administering growth factors significantly shortened the
healing time of acute skin wounds, including superficial burn injuries [mean difference (MD) = −3.02; 95% confidence interval (CI): −3.31 *−2.74;
Biologic Transducers in Wound Healing 83
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p < 0.00001], deep burn injuries (MD = −5.63; 95% CI: −7.10 * −4.17;
p < 0.00001), traumata and surgical wounds (MD = −4.50; 95% CI: −5.55 *
−3.44; p < 0.00001). Growth factors increased the healing rate of acute skin
wounds and decreased scar scores. The incidence of adverse reactions was lower in
the growth factor treatment group than in the non-growth factor group. A systematic
review and meta-analysis was showed growth factors not only are effective and safe
for managing ki
nds of wounds, but also accelerated their healing with no severe
side effects (Wei et al. 2022).
In 1998, Fu and his team adopted multi-centers and controlled clinical trial,
observed the effects of bFGF on wound healing and any side effects. 1024 cases
with acute and chronic wounds such aspressure ulcers, draining sinus, and some
acute wounds were treated with
bFGF. The healing time of wounds was reduced by
3–4 days in therapy group with bFGF compared with the control group. The
successful rates from bFGF on promoting the wound healing for chronic dermal
ulcers was 93.5%. There was no side effect (Fu et al. 1998). And then they had
another clinical study showed that rbFGF could accelerate granulation tissue formation and re-epithelialization, improved the quality of healing (Fu et al. 1998). In
2001, an original finding was discovered by Fu's and his team, and published in the
Lancet, that epidermal cells undergo dedifferentiation after growth factor intervention, sheds new light on wound healing theory (Fu et al. 2001).
In 1997, Robson has argued that using exogenous growth factors for the treatment chronic wounds holds great therapeutic potential (Robson 1997). Whereafter,
although part of clinical studies of recombinant growth factors used to treating
chronic ulcers seem reported disappointing outcomes. Many factors might be
intervene healing process of chronic wounds. When clinical trials are undertaken in
which these factors are incorporated in the study design will the true potential of
various growth factors be appropriately determined (Fu et al. 2005).
Several randomized controlled trials confirmed the efficacy of each of the
above-mentioned agents. The meta-analysis comparing growth factors were used in
DFU from which the Cochrane Wounds Group concluded that the exogenous
growth factors could improve wound healing, such as EGF, PDGF, PRP, etc. Many
other factors, such as offloading, infection control, ischemia improve, and glycemic
management, etc. system disorder must also be taken into think over, along with
local wound management (Pino-Sedeno et al. 2019; Bui et al. 2019; Zhao et al.
2014).
In 2020, Mahdipour identified 26 RCTs involving diabetic ulcer patients that
evaluated the effectiveness of platelet-derived growth factor, epidermal growth
factor, fibroblast growth factor, granulocyte colony-stimulating factor, vascular
endothelial growth factor (VEGF), transforming growth factor (TGF), erythropoietin, and talactoferrin (a recombinant human lactoferrin). The main outcome was
complete healing though different indices were employed to define this such as
wound closure, granulation tissue formation, or complete re-epithelialization. There
is a greater agreement on the effectiveness of GF to enhance the healing of diabetic
ulcers. However, it is suggested that some RCTs assessing the different combinations of cytokines/growth factors are indicated (Mahdipour and Sahebkar 2020). At
84 B. Cheng and X. Fu
the same year, the Chinese Burn Association published the clinical guideline about
topical growth factors for skin wounds, which indicating efficacy, application
details, adverse reactions and precautions of five clinically common topical
exogenous growth factors or cytokines using the Grading of Recommendations
Assessment Development and Evaluation (GRADE) method. In order to promote
the rational application of topical exogenous growth factors in skin wounds a
nd to
benefit more patients. Until 31 July 2019, among these, 40 were on bFGF, of which
33 were in Chinese and 7 were in English; 7 were on aFGF, of which 6 were in
Chinese and 1 was in English; 44 were on EGF, of which 35 were in Chinese and 9
were in English; 11 were on GM-CSF, of which 4 were in Chinese and 7 were in
English; 7 were on PDGF, all of which were in English. In this clinical guideline,
topical application of exogenous growth factor could be used in different types of
chronic woun
ds, it is different about quality of evidence and Grading of Recommendations Assessment. Such as in diabetic foot ulcers, the quality of evidence of
aFGF and GM-CSF is low, recommendation is weak. the quality of evidence of
bFGF and PDGF are moderate, recommendation also are weak. EGF’s the quality
of evidence is high, recommendation is strong. However, in other chronic wounds
(such as venous ulcers), the grade the quality of evidence forming and recommendation are ent
irely different (Han et al.
2020)
.In future, the need remains for
more better designed studies to further strengthen the evidence and ensure the level
of recommendation.
In 2022, Lee and his colleagues introduced about chronic venous leg ulcers
(VLU) treatment with growth factors. This systematic review and meta-analysis
evaluates the impact of growth factor treatments of VLU in comparison to control
for complete wound heali
ng in the past two decades. From electronic databases and
searches, 13 RCTs met the eligibility criteria. There was a significant difference
among a sort of growth factors (for example concentrate platelets, KGF-2, TGF-b,
EGF, CGF, GM-CSF) and placebo group in wound healing (p = 0.04). Every
growth factor compared to placebo significantly increased the healing rate of
wounds. The article focused on the percent reduction in wound area, healing time,
and adverse events. There was no difference in overall adverse event rate. Most
comparisons have low certainty of evidence according to Grading of Recommendations, Assessment, Development, and Evaluation. This meta-analysis suggests
that growth factors have a beneficial effect in complete wound healing of VLU.
Growth factors may also increase percent reduction in wound area. The suggestion
of benefit for growth factors identified in this review is not a strong one based on
the low quality of evidence. In addition, future trials should minimize risk of bias by
including larger populations using double-blind placebo controlled design and
should also measure percent wound healing as their outcome to properly evaluate
the effectiveness of growth factors on VLU treatment (Lee et al.
However
, due to the absence of head-to-head clinical trials comparing all the
2022).
different types of available growth factors used topically in the management of
DFU. This might be accounted as a reason for disagreement in the results of trials.
Moreo
ver, various possible confounders are present in studies such as wound size,
type of dressing, gender, age, and overloading or offloading. Studies considered
Biologic Transducers in Wound Healing 85
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their groups to be approximately the same for age and sex. However, differences in
wound size has been wide and few tri als have analyzed the effect of this covariate
on the healing rate. Topical administration of growth factors after debridement is a
promising approach to enhance wound healing because of their deficiency or a
noticeable deterioration (such as overloading of bacterial community) of quality in
chronic wounds (Figs. 3 and 4).
Fig. 3 The right ankle of DFU was treated with recombinant aFGF. One month later, wound bed
improved significantly and began to re-epithelialized (Chen Junyang supply)
Fig. 4 The anterior tibial ulcer was treated with recombinant aFGF powder, once a day. After
5 weeks, hard-to heal wound have healed completely (Zhang Chengshu supply)
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