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96 B. Cheng and X. Fu
(SMCs), glial cells, Mucosal epithelium and chondrocytes. EGF exerts chemotaxis
and mitogenic effects mainly by binding to receptors on the cell membrane and
forming a complex signal pathway during its intracellular transmission, resulting in
the regulation of cell metabolism, differentiation and other biological activities.
Based on literature literature, specialist of wound healing inferred and verified that
EGF can promote the healing of vario
us kinds of skin and soft tissue defects.
In 1992, a double-blind randomized study conducted at a single center was used
observed that recombinant human epidermal growth factor (rh-EGF) treat 44
patients with venous ulceration of the lower extremities. An aqueous solution
(10 lg/mh) of rh-EGF was applied topically to the ulcers, twice a day until healing.
On the basis of this study findings, the authors thought using rh-EGF for chronic
wound with in the dose and manner was safe. Althought failed to significantly
enhance reepithelialization of venous ulcers. A greater reduction in ulcer size and a
larger number of healed ulcers with the use of rh-EGF are be worth looking forward to results (Falanga et al. 1992).
In 2014, Gomez-Villa (2014) investig ated the efficacy and safety of rhEGF in
patients with diabetic foot ulcer (DFU). A randomized, two-center, double-blinded,
placebo-controlled study was conducted comparing a thrice-per-week intralesional
application of rhEGF (75 lg) or vehicle (placebo) in patients with DFU for
8 weeks, three times per week. Most of DFU were stage IIIA, B and stage IIB. All
patients received standard care, which included a complete physical examination
and consultation by an internist. The number of completely healed ulcers, size, and
wound bed characteristics were evaluated to determine the efficacy of rhEGF with
Student’s t test. Intralesional rhEGF could promoted the epithelialization of the
wound bed, and significantly reduced the area of the DFU treated. Therefore,
rhEGF r
ed in better outcomes for patients suffering from DFU. The only
esult
adverse event that we observed more frequently in the rhEGF group was dizziness,
not identified a mechanism to explain why dizziness occurred.
Yang et al. (2016) topically used recombinant human epidermal growth factor
(rhEGF) on the ulcers of diabetic foot. This systematic review and meta-analysis
was designed to evaluate if rhEGF increased the complete healing rate of diabetic
foot ulcers compared with the control. This searched the MEDLINE, Cochrane
Library, EMBASE, and Web of Knowledge databases (up to December 22, 2015).
Studies were identified and selected, and data were extracted by 2 independent
reviewers. The initial search identified 399 articles. they also hand-searched 12
articles from reference lists of relevant review articles.. All statistical analyses were
performed using Review Manager Meta-Analysis software, version 5.1 (The Nordic
Cochrane Centre, The Cochrane Collaboration; http://ims.cochrane.org/revman).
The studies
evaluated the rate of healing of diabetic foot that were treated with
rhEGF or controls (placebo). On account of study heterogeneity, a random-effects
model was performed, and the combined odds ratio (OR) indicated a significantly
greater complete healing rate in patients treated with rhEGF compared to placebo.
These results indicate that rhEGF is beneficial in the treatment of diabetic foot
ulcers by increasing the rate of wound healing. These findings provides evidence
for a significant effect of rhEGF in treating diabetic foot ulcers. In future, the studies
Biologic Transducers in Wound Healing 97
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should be assess the effects of rhEGF alone or in combination with other growth
factors or wound dressing agents.
In 2019, Bui et al. (2019) published a meta-analysis (registration number
CRD42019126404) that was performed to synthesize the evidence of rhEGF
treatment in DFUs in comparison to placebo. Databases included for the search
were PubMed, EMBASE, the Coc hrane Library, Web of Science, EBSC Ohost,
ScienceDirect, and Scopus (up to 10 January 2019). A randomized,
placebo-controlled trials evaluating the effects of rhEGF administration, for
example intralesional injection, topical-gel, crea
m using for patients with DFUs.
The outcome of interest was the complete healing rate of DFUs. Quality of evidence
on the complete healing rate was estimated using the Grading of Recommendations
Assessment, Development, and Evaluation (GRADE) approach. The Stata/IC
software (version 15.1, StataCorp LL, College Station, Texas, USA) was used to
make a funnel plot and Egger’s regression test. The results showed that combined
OR (intralesional injection and topical apply) was 4.005 (95% CI: (2.248; 7.135),
p < 0.001). The ORs for intralesional injection and topical application were 3.599
(95% CI: (1.213; 10.677), p = 0.021) and 4.176 (95% CI: (2.112; 8.256),
p < 0.001), respectively. Statistical heterogeneity might not be important in overall
treatment and both of the subgroups. They results support the application of rhEGF
using for DFUs. However, the GRADE approach on rhEGF treatment is low evidence. Hence, the effect estimate of rhEGF may be limited, and the true effect may
be substantially different from the estimate effect. At the same time, the amount of
data on adverse effects was also limited. The study emphatically point out wound
care is a key step throughout the treatment process, but it is not enough. Many other
factors, for example control of infection, ischemia, and blood glucose, offloading,
must also be seriously consideration, along with local wound management.
In 2020, Yang et al. (2020) finished a meta-analysis of the efficacy and safety of
topical recombinant human epidermal growth factor (rhEGF) on the treatment of
diabetic foot ulcers. The authors conducted a comprehensive review of PubMed,
EMBASE, Cochrane Library databases, and Web of Science (up to November 30,
2018). Seven randomized controlled trials (RCTs) that involved 610 participants
were included in this review. These results were analysized with RevMan 5.3
software. The pooled results showed that topical rhEGF could significantly promote
the healing of diabetic foot ulcers. Topical application of rhEGF could promote ulceration healing of diabetic feet of Wagner grade 1 or 2 significantly,
and intralesional injection of rhEGF appeared to promote the healing of more
severe ulcers. The quality of the evidence was low due to unclear risk of bias in the
original trial and moderate statistical heterogeneity. The statistical result displayed
that there is no significant difference in the incidence of advers e events between the
rhEGF treatment group and the control group.
Oliveira and his colleagues (2021) investigated whether the addition of recombinant human epidermal growth factor (rh-EGF) to 2% carboxymethyl cellulose gel
is more effective in diabetic wound healing than standard treatment (the best
standard of usual care available either alone or in addition to the intervention), a
pilot, double-blind (patient and statistician), randomized (1:1 ratio) and controlled
98 B. Cheng and X. Fu
clinical trial (NCT12616798, Brazil ian) with therapeutic intervention was performed at a university hospital. All sample contained 25 patients (14 in the intervention group with using rh-EGF (4 ppm) and 11 in the control group with using
2% carboxymethyl cellulose gel) with diabetic wound or a chronic venous ulcer,
from 2 cm
and analyzed by intention-to-treat
2
to 100 cm2, time longer than 12 weeks. Data were tabulated in SPSS
approach, without loss or exclusion of participants. Twenty-five subjects participated with a mean age of 60.6 years, a predominance of males in both groups and 100% prevalence of type-2 diabetes. Within
12 weeks, complete wound healing occurred in three ulcers in the intervention
group versus one ulcer in the control group. The percent reduction in the wound
area was significantly higher in the intervention group than in the control group
(p = 0.049). About the types of tissue, increase of granulation and epithelialization,
and a reduction of exudation wer e observed in both groups. Decreased slough
occurred only in the intervention group. No participant experienced serious or local
adverse events during the study period. This study showed that rh-EGF is effective
and safe treatment for chronic wounds, with a statistically significant reduction in
wound area, improvement of tissue quality.
Combination Application of Growth Factors in Chronic Wound
Wound healing is a complicated process that comprises of various cytokines and
growth factors which play roles in a repair signal pathway, it is not surprising that
single growth factor therapy outcome in not remarkable benefits. To move forward
in optimising growth factor delivery to wounds, especially ulcer, some research
investigated the ways for delivering individual or combinations of growth factors.
In 2000, Robson compared the healing response of sequential topically applied
cytokines to that of each growth factor or cytokine alone and to a placebo-treated
patients with pressure ulcers, and to evaluated the molecular and cellular responses.
Because of a deficiency of growth factors and cytokines in chronic wounds and the
reversa
performed with several exogenous growth factors/cytokines application. Because
single growth factor therapy has not been uniformly successful in therapy pressure
sore, combination or sequential cytokine or/and growth factor treatment has been
proposed. Laboratory data have suggested that sequential treatment with
granulocyte–macrophage/colony-stimulating factor (GM-CSF)/basic fibroblast
growth facto
A double-blind, randomized, placebo-controlled pressure ulcer trial was performed
comparing sequential GM-CSF/bFGF therapy with that of each cytokine alone and
with placebo during a 35-day period. The primary measure was wound volume
decrease over time. Level of cytokine/growth factor in wound were serially
determined. Ulcers treated with cytokines and growth factor had greater closure
than those in placebo-treated patients. Patients treated with bFGF alone did the
best, followed by the GM-CSF/bFGF group. Although more than 85% wound
closure appeared to distinguish cytokine/growth factor-treated wounds from those
f impaired healing in animal models, pressure ulcer trials have been
l o
r (bFGF) might augment the previ ously reported effect of bFGF alone.
Biologic Transducers in Wound Healing 99
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treated with placebos, and a statistically greater number of bFGF-treated patients
achieved more than 85% closure, only quarter of all the patients had more than 85%
wound closure. The reason may be due to the only 35-day treatment
period (Robson et al. 2000).
In future, combination application of growth factors/cytokines for chronic
wound should be focus their temporal and spatial characteristics in the process of
wound (e.g. waterfall versus slow release), protect the growth factor from degradation and provide tissue concentrations consistent with wound repair and
regeneration.
Effectiveness of (Stem) Cells for Skin Chronic Wounds
Wound healing has been greatly challenging in different chronic refractory ulceration. Among them, nonrevascularizable critical limb ischemic ulcers, venous leg
ulcers, and diabetic neurovascular ulcers are well-known refractory skin defects that
are difficult toheal within reasonable periods. Cellular therapy, characterized by
using cells from diverse sources, with self-renewing potential and
multi-differentiation ability, has shown promise in the management of chronic
wounds. Partly differentiated, progenitor cell-based graft transplantation or direct
injection of autologous stem cells might promote the wound healing. In 2021,
Dong’s studies aiming to comprehensively analyzed the effects of cell therapy on
skin wound healing could provide clinical evidence for skin defects treatment.
Different databases (Science Direct, Springer Link, Web of Science, ProQuest, and
Network Digital Library, Cochrane Central Register of Controlled Trials, etc.) were
searched for full-text publications on the comparison between (stem) cell therapy
and regular therapy, from January 2000 to March 2020. After a long-term
follow-up, fewer patients underwent major amputati on in the cell-therapy group,
compared with the standard therapy group, and those in the cell therapy group were
characterized by a smaller ulcer area. Moreover, there was a significant difference in
the wound healing rate between the intervention and control groups. However, pain
caused by skin wounds was hardly mitigated by cell therapy in patients with critical
limb ischemia. In this study, cell therapy proved effective in decreasing the size of
ulcers and improving the wound closure rate. Additionally, the rate of major
amputation was significantly decreased in the cell therapy group, compared with the
normal treatment. However, the symptoms of pain were hardly alleviated by cell
therapy in patients with cutaneous ulcers caused by peripheral artery disease-related
critical limb ischemia (Dong et al. 2021).
Autologous stem cell therapy (ASCT) has emerged as a promising alternative
treatment for those who suffered from Lower extremity chronic wounds (LECWs).
Chiang and his colleagues (Chiang et al. 2021) assessed the effects of ASCT on
LECWs with the Preferred Reporting Items for Systematic Review and
Meta-Analyses (PRISMA) guidelines and PROSPERO CRD42021248746. The
authors searched three core databases (PubMed, Embase, and Cochrane Controlled
100 B. Cheng and X. Fu
Trials Register), and independently identified evidence according to predefined
criteria. They also individually assessed the quality of the included randomized
controlled trials (RCTs) (up to December 2020), and extracted data on complete
healing rate, amputation rate, and outcomes regarding peripheral circulation. The
extracted data were pooled
using a random-effects model due to clinical heterogeneity among the included RCTs. A subgroup analysis was further performed
according to etiology, source of stem cells, follow-up time, and cell markers. This
systematic review and meta-analysis of RCTs were conducted following the recommendations of the Cochrane Collaboration, and were reported according to the
Preferred Reporting Items for Systematic Review and Meta-Analyses Protocols
(PRISMA-P) guidelines. ASCT through intramuscular injection can significantly
improve wound healing in patients with LECWs caused by either DM or critical
limb ischemia. The results showed significantly increased values of Ankle brachial
index (ABI) and transcutaneous oxygen pressure (TcPO
) levels (indicating better
2
perfusion and higher levels of tissue oxygen available for healing), which were
meaningful to confirm the improvements of total and major amputation rates and
wound healing rate. ASCT significantly and similarly increased the complete
wound healing rates in patients with either DM. The intramuscular subgroup had a
significantly higher complete wound healing rate than the intra-arterial subgroup. Moreover, intramuscular injection seems to be a rather safe choice for
administration. However, more extensive scale and well-designed studies are necessary to explore the details of ASCT and chronic wound healing.
Shu a
ed the current evidence regarding the efficiency and potential
ssess
advantages of stem cell-based therapy compared with conventional standard
treatment and/or placebo in the treatment of diabetic foot ulcer . A comprehensive
search in PubMed, EmBase, Cochrane Central and Web of Science databases was
conducted during December 2016 and a systematic review and meta-analysis of all
relevant studies were performed. A total of 7 studies that involved 224 diabetic foot
patients, classified as Wagner grades 1–5, were analyzed. The pooled results confirmed the benefits of using the stem cell treatment. Partial and/or complete healing
were significantly faster in the stem cell group compared with the control group.
The present meta-analysis indicates that stem cell-based therapy can enhance the
healing of diabetic foot ulcers and is associated with lesser pain, low er amputation
rate and improved prognosis compared with normal treatment. Larger sample sizes
and thorough clinical research are required in order to determine whether the
source, the dose and/or the delivery method of stem cells are key factors for the
successful accomplish of the process. In future, well-designed randomized controlled trials are required to confirm and update these findings (Shu et al.
Althoug
h primary studies in animal models and humans have showed the
2018).
therapeutic potential of autologous stem cell help to accelerate healing of
chronic wounds. The results of pilot randomized controlled trials (RCTs) in humans
have been inconsistent. A systematic review and meta-analysis of RCTs was performed to evaluate the role of autologous stem cell-based therapy (derived either
from bone marrow or from peripheral blood) for lower extremity ulcers. Studies
identified during a systematic search of Pubmed, Embase, Cochrane's library,
were
Biologic Transducers in Wound Healing 101
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and references cited in related reviews and studies. Studies were included if they
were RCTs published in English, recruited patients with lower extremity ulcers who
were assigned to either a group for the topical therapy with autologous stem cells, a
control group (with no treatment or placebo), and reported data regarding the
healing of the chronic
wounds. Overall, autologous stem cell-based therapy was
associated with better healing of lower extremity ulcers with little heterogeneity.
Moreover, autologous stem cell-based therapy was associated with a greater
reduction in ulcer size. Subgroup analyses indicated that stem cells from peripheral
blood and bone marrow seemed to exert similar beneficial effects on the healing of
ulcers. Stem cell therapy was not associated with any increased risks for
procedure-related adverse events. The optimized sources, amounts, and delivery
methods of stem cell-based therapy for patients with chronic lower extremity
ulcers need to be determined, and the long-term effects of stem cell-based therapy
on clinical outcomes need further investigate. Autologous stem cell-based therapy
is effective and safe for improving the healing of chronic lower extremity ulcers,
and large-scale RCTs are needed to confirm the findings (Jiang et al. 2016).
Accumulating evidence from basic science studies and clinical trials have
pointed out that cellular therapy could focus on multiple facets during chronic
wounds (like diabetic foot ulcer) healing disorder through dysfunction of cell
proliferation, vascularization, neuro-restoration, inflammation regulation, exosomes
synthesis, and others. A meta-analysis of randomized controlled clinical trials
evaluated and synthesized clinical evidence, its aims to estimate the therapeutic
efficacy of cellular therapy for diabetic foot ulcer compared to standard therapy. The
results showed cellular therapy seemed to be safe and effective treatment of diabetic
foot ulcer, associated with a higher ABI, TcPO
, more reduction in pain, decreased
2
amputation risk, and with no serious complications and low risk of short-term slight
complications (Zhang et al. 2017b).
Outlook
The aim of this chapter was to review the value that biological transducers bring to
chronic wound management. Although many aspects of the healing process are
influenced by many factors, the obstruction of cytokines and growth factors formation may be a major factor of chronic wound healing disorder. Even with
cytokines/growth factors present, wound cells might be unresponsive due to a lack
of cell surface receptors. Therefore, if chronic ulcer is to healing, we must be to
supply more cytokines/growth factors (Cheng and Fu 2018) together with mainstay
treatment as in standardized care. Mainstay treatment for venous leg ulcers is
compression, for neuropathic diabetic foot ulcers is offloading and for ischemic
diabetic foot ulcers, it is revascularization. Highlighted mainstay is an essential
aspect of chronic wound treatment.
102 B. Cheng and X. Fu
To overcome this unmet need, therapeutic growth factors has evolved in attempt
to increase repaired cells
proliferation, migration, differentiation in injury sites. One
unavoidable and important problem involves the local protease-rich environment of
a chronic wound, which has been shown to actively degrade and inactivate most
growth factors. This finding may explain in part the altered levels of growth factors
in chronic wounds, but it also suggests that topical therapeutic applications probably allow only a brief suboptimal exposure of the wound to the growth factor
unless the protease-rich, pro-inflammatory wound environment is first addressed.
Drug delivery strategies suffer from the inherent loss of drug activity due to the
combined effects of physical inhibition and biological degradation. In order to
overcome the limitations of topical using recombinant growth factors or peptides, a
molecular genetic approach in which genetically modified cells synthesize and
deliver the desired growth factor in a time-regulated manner is a powerful
means. Recently, two multicenter, double-blind, placebo-controlled clinical trials in
Japan (phase III) and US (phase II) demonstrated that hepatocyte growth factor
(HGF) gene therapy for CLI significant improved primary end points and tissue
oxygenation up to two years in comparison to placebo. These clinical results
implicate a distinct action of HGF on cellular processes involved in vascular
remodeling under pathological condition. This review presents data from phase I-III
clinical trials of therapeutic angiogenesis by gene therapy in patients (Sanada et al.
2014).
In addition, current investigations are studying the combination of growth factors, the improvement of growth factor vehicles, the utilization of tissue engineering
constructs with growth factors, the interaction of stem cells in conjunction with
growth factors, and gene therapy modalities.
Future successful therapeutics for chronic ulcers will likely parallel the development of effective therapies for nonhealing wounds as a whole. A new generation
of growth factor therapy may very well be on the horizon for these wounds, which
the therapeutics will likely need to be integrated into a combination therapy to be
most effective.
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