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22 Evidence-Based andClinical Experimentation onCell Therapy
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techniques [16]; moreover, in this developing matter, the regulations on cell manipulations can differ between countries, thus limiting the com­parability between different clinical studies.
Clinical applications of cell therapy increased over the latest decades, following a surging num­ber of types and qualities of cell lines studied. Stem cells are currently used in numerous medi­cal branches, including neurology, cardiology, hematology, and plastic surgery [15–17].
This chapter is aimed at presenting a brief synopsis of clinical experimentations regarding cell therapy in the management of ulcers.
22.2 Cells Suitable forCell
Therapy
Stem cells are undifferentiated, self-renewal, clonal cells able to differentiate into multiple cell lines. They can be found in every stage of life (embryonic, fetal, and adult) and can be classi­ed based on their differentiation grade and thus their ability to generate multiple cell types [18]; totipotent cells are the least differentiated cells, and they are capable of forming both embryonic and extraembryonic tissues, and pluripotent cells can give rise to cells from all of the three germ layers (endoderm, ectoderm, and mesoderm), multipotent cells can only generate cells proper of a single germ layer, and nally oligopotent cells are the most similar to adult cells and are able to form limited cell types of a tissue. In adult life, stem cells can be found in differentiated tis­sues and organs, playing a key role to repair the injury in case of tissue damage, as well as regu­larly proliferating in certain tissues—for instance, skin, bone marrow, or liver—to supplement cells during normal cellular turnover [19, 20].
22.2.1 Pluripotent Stem Cells
Induced pluripotent stem cells (iPSCs) are recently described as stem cells generated via genetic reprogramming from broblasts using dened retroviral transcription factors [18, 21].
iPSCs were shown to maintain the ability to gen­erate cell lines from each of the three germ lay­ers, a characteristic proper of PSCs [22]. Compared to allogenic stem cell transplantation, using iPSCs technology permits to harvest the patient’s own somatic cells, reprograming them to obtain iPSCs, and then expanding them to treat the same patient with autologous pluripotent stem cell transplantation, thereby reducing the need for immunoprotected regimens when com­pared to allogenic stem cell transplantation [23]. Along with their great potential, iPSCs are reported to be genetically instable, thus at risk of tumor generation; the main focus of current clini­cal experimentations is the development of safety protocols to increase genomic stability [24]. Despite these issues and complexity, iPSCs derived from somatic endothelial cells showed remarkable results in murine models compared to human umbilical vein endothelial cells (HUVECs) or somatic endothelial cells from the same type in terms of revascularization capacity and lymph-vasculogenesis and lymphangiogene­sis [25, 26].
22.2.2 Embryonic andExtraembryonic Stem Cells
Placental stem cells (PSCs) and Umbilical cord stem cells (UC-MSCs) are extraembry-
onic stem cells capable of high proliferation and differentiation properties due to signicant telomerase expression. These characteristics permit rapid culture and thus large quantities available compared to adult tissue-derived MSC. Moreover, UC-MSCs are at low risk of graft rejection in case of allogenic stem cell transplant, thanks to anti-inammatory and immunomodulating properties [27]. PSCs also showed promising results in rats and mice in terms of clinical improvement of wound healing and laboratory ndings of higher levels of inte­grin β1, integrin β3, and a decrease in ICAM expression compared to controls after intrader­mal injection [28, 29].
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22.2.3 Adult Stem Cells
As mentioned before, it is well known that sev­eral adult tissues have the ability to repair dam­aged structures and cells autonomously. Renewal of adult tissue cell lines is possible thanks to adult stem cells, also known as progenitor cells. The differentiation potential of adult SCs was once assumed to be strictly limited to the same specialized cell lines found in the tissue of origin (i.e., bone marrow, skin, and liver). This belief initially extinguished the enthusiasm for the use of these cells in treatment and therapy. During the past few years, however, several studies have shown the potential of adult SCs to proliferate and differentiate into new cellular identities, thanks to the expression of markers of multipo­tency previously seen in pregastrulation embry­onic cells [19]. This capability is known as stem cell plasticity, a nding that has fueled the devel­opment of numerous studies on the use of adult stem cells in regenerative medicine. Several adult stem cell types have been studied for wound heal­ing because of their capacity to improve vascu­larization not only differentiating into vascular cells but also thanks to their paracrine effects and immune response modulation properties.
Mesenchymal stem cells (MSCs) are one of the most studied stem cell types in cell therapy. MSCs give rise to all skeletal tissues, as they are multipotent, self-renewing, post-natal cells found in adult tissues (i.e., adipose tissue, dental pulp and gingiva, blood and bone marrow, cartilage, synovium, and periosteum) and both embryonic and extraembryonic tissues (that include the umbilical cord, amniotic uid, and placenta) [30]. In particular, their role in wound healing seems to be related more to the production of various growth factors and cytokines that are fun­damental for inducing cell proliferation and migration; furthermore, these cells are able to control inammation during skin regeneration. Importantly, MSCs secrete VEGF, thereby stimu­lating the angiogenic process [14]. Underlying the importance and power of cell therapy, in recent years MSCs were found to be both de­cient and defective in animals and patients with diabetes or chronic wounds. These ndings cor-
roborate the importance of a direct delivery of healthy functional MSCs to overcome this de­ciency and achieve a proper wound healing [10].
Among MSCs, bone marrow-derived mes- enchymal stem cells (BMSCs) are promising cells for wound healing, thanks to their plasticity and morphological characteristics. BMSCs are adult multipotent stem cells able to proliferate expressing neuroectoderm, mesoderm, and endo­derm characteristics in vitro [31]. These cells showed good wound healing potential in full­thickness ulcers, showing smaller wound size, higher blood vessel density, and reduced inam­mation after treatment in a study on rat model by An etal. [32].
Human adipose-derived stem cells (ASCs or ADSCs) are another fundamental type of MSCs. Since the adipose tissue is an easily accessible autologous source, these cells are widely used in cell therapy. Most often, cells are isolated from the so-called stromal vascular fraction (SVF), which is obtained by collagenase-mediated digestion of the adipose tissue. The SVF contains multiple cell populations, including stem cells (ADSCs and hematopoietic stem cells) and mature cells (broblasts, myoblasts, endothelial cells, pericytes, and blood cells), in addition to growth factors and cytokines [14]. The therapeu­tic potential of the SVF was tested in animal models of difcult wounds and resulted in accel­erated wound healing through increased bro­blast proliferation, vascularization, and reduced inammation [33, 34].
22.3 Evidence onApplicability
ofCell Therapy inUlcer Management
Several clinical trials have been performed on autologous cell-based therapy. The application of isolated and cultured multipotent cells to the wound bed is a critical step, as cells tend to be rapidly washed out. Thus, the use of an appropri­ate scaffold to support cell seeding and engraft­ment is recommended.
The use of commercial biocompatible scaf­folds or dermal substitutes in regenerative medi-
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cine has been widely investigated, and several research groups are currently developing new biomaterials. A relatively new eld of study involves the combination of scaffolds and cells to support revascularization [35, 36]. The main cell types used in this setting are keratinocytes, bro­blasts, and ADSCs.
In a phase I clinical trial, Meuli demon­strated that an hydrogel seeded with autolo­gous keratinocytes isolated from pediatric patients can be used safely [37]. More recently, Carstens etal. demonstrated the safety and the efficacy of the treatment of chronic diabetic foot ulcers with adipose-derived SVF cell injections [38].
The ADSCs contained in SVF fraction repre­sent one of the most employed adult stem cell therapy due to their multipotency and the use of this stem cell population showed to have promis­ing potential because of the yield of their MSCs, which is 40x higher than that of BMSc, and their ability to maintain their diploid karyotype for one hundred generation of culture.
Multiple mechanisms contribute to the pro­healing activity of the SVF, which include:
1. Direct differentiation of SVF cells into bro-
blasts [39], keratinocytes [40], and endothe­lial cells [41].
2. Production and the secretion of molecules that induce cell proliferation, differentiation, angiogenesis, and control the balance between pro- and anti-inammatory factors, such as basic broblast growth factor (bFGF), insulin­like growth factor 1 (IGF1), hepatocyte growth factor (HGF), VEGF, transforming growth factor beta-1 (TFGβ1), and keratino­cytes growth factor (KGF).
In vivo studies mainly relied on rodent models (except for a few rare different animal models CIT) and demonstrated pro-angiogenic responses, the ability to induce regeneration, muscle repair, attenuation of scarring with antiaging effect, and collagen deposition and organization.
The therapeutic potential of the SVF has been described in several clinical studies focused on: musculoskeletal conditions (joint, bone, and ten­don) [42], breast reconstruction [43], chronic myocardial ischemia [44], skin rejuvenation [45], inammatory and immune diseases [46, 47], and non-healing wounds of various underlying etiol­ogies (post-traumatic, diabetic, systemic sclero­sis, perianal stulas, critical limb ischemia, and radiodermatitis) [38, 42, 48–51].
Most of the studies deal with venous ulcers and evaluate the effect of cell application in terms of clinical improvement and rate of healing.
Randomization
Author
1 Raposio
Et al. [62]
2 Chopinaud
etal. [63]
3 Han etal.
[59]
4 Marino
Et al. [60]
5 Carstens
Et al. [48]
6 Carstens
Et al. [38]
and blinding n. patients Cells used Characterization Yes, open
label
No, open label Pilot study
Yes, open label Pilot study
No, open label
No, open label
No, open label phase I
16 cases 24 controls
10 cases 0 controls
26 cases 28 controls
10 cases 10 controls
10 cases 0 controls
63 cases SVF In vitro cell
ADSC + e-PRP
ADSC None Injection Hypertensive
ADSC In vitro
ADSC In vitro FACS Injection Arterial ulcers
SVF In vitro
None Topic injection Leg ulcers
Co-cultured broblast
Cell count
count
Application method Target
(venous, arterial, mixed)
ulcers
Topic Diabetic foot
Injection Arterial ulcers
Injection Diabetic
ulcers
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Randomization
Author
7 Sharaf
etal. [64]
8 Lee, Park
etal. [65]
9 Zollino
etal. [49]
10 Bura etal.
[61]
11 Lee etal.
[51]
12 Bourne
Et al. [66]
and blinding n. patients Cells used Characterization No, open
label
No, open label
Yes, open label Phase II
No, open label Phase I
No, open label Pilot study
No, open label
15 cases 0 controls
19 cases 0 controls
100 cases 100 controls
7 cases 0 controls
15 cases 0 controls
5 cases 0 controls
ASC In vitro Lipolling Head and neck
SVF None Injection Scar revision
CAT (centrifugated adipose cells)
ADSC cultured (8days)
ADSC cultured
Fat graft SVF In vitro,
In particular, markers such as pain variation and increase inlocal vascularization were evalu­ated in patients with peripheral artery disease, using different methods, including echo-Doppler, angiography, thermographic assessment, and transcutaneous oximetry.
The SVF is generally collected via standard liposuction, which entails a small incision to inltrate a solution, and consequently lipoaspira­tion via cannulas connected with negative pres­sure systems. For this reason, clinical studies on SVF could be biased by differences between local protocols of preoperative site preparation and inltration solution before fat harvesting [52,
53].
Moreover, the adipose tissue could be col­lected via liposuction from different body dis­tricts, as abdomen, hip, lumbar, pertrochanteric, or inner thigh region, and anatomical differences along with donor gender, age, body mass index, and the presence of chronic diseases can inu­ence the therapeutic effect. For instance, the fat harvested from female donors seems to have a higher level of cytokines and growth factors due to the hormonal effect of estrogens, whereas older age and comorbidities negatively inuence the potential therapeutic effect [54]. Finally, there
Application method Target
reconstruction
In vitro Injection Leg ulcers
Yes Intramuscular
injection
Yes Intramuscular
injection
Injection Amputated cultured but not re-injected
Peripheral artery disease
Peripheral artery disease
legs
is no consensus on the optimal method for SVF harvesting, although low negative pressure suc­tion via larger cannulas seems to increase adipo­cyte viability compared with other liposuction techniques [55]. The adipose tissue, harvested both through lipoaspiration or direct excision, necessitates further processing using either enzy­matic digestion via collagenase or via mechani­cal cell separation.
The clinical use of SVF for the treatment of difcult wounds is currently limited by the GMP standards that are required. Indeed, cells must be harvested and cultured under GMP conditions, using GMP-grade reagents and methods. This limits the possibility of precisely characterizing the cells prior to their transplantation. On the same line, the use of collagenase and centrifuga­tion are considered a potential source of contami­nation and are banned in many countries, thus representing an issue leading to a difcult FDA approval [56, 57].
For this reason, in some countries the use of SVF in clinical practice appears to be limited to “tissue SVF” (tSVF), which is a less puried cell population (as it simply derives from a mechani­cal separation of the SVF itself from the adipose tissue) compared with the cellular SVF (cSVF),
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which derives from enzymatic digestion and is therefore a more selected cellular population.
In conclusion, despite the promising effect of the SVF fraction on wound healing, several aspects could be still optimized, such as cell isolation proto­col, expansion, and administration [58]. In addition, most of the studies performed so far show major limitations, as none of them was blinded, with con­sequent lack of objective results, only a few of them were randomized and the cohort of patients was invariably of small size [48, 51, 59–62].
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50. De La Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A.Expanded allogeneic adipose-derived stem cells (eASCs) for the treat­ment of complex perianal stula in Crohn’s disease: results from a multicenter phase I/IIa clinical trial. Int J Color Dis. 2013;28:313–23. https://doi.org/10.1007/
s00384- 012- 1581- 9.
51. Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, Park JH, Lee SY, Kim SP, Kim YD, etal. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. Circ J. 2012;76:1750–60. https://doi.org/10.1253/
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Bioinductive Dressing
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FrancescoD’Andrea andFrancescaMosella
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23.1 Introduction
Bioactive dressings (BD) are still a topic of dis­cussion in order to reach a proper denition. To date, they are dened as dressings of natural or synthetic origin capable of interfering with the reparative process by direct or indirect mecha­nisms [1].Their action is extrinsic either through the release of bioactive factors or because they consist of materials with endogenous activity. Among these we can include alginates, colla­gens, hydrocolloids, biotextiles, chitosan, chitin, and their derivatives.
Such a broad denition means that almost all advanced dressings can be included in this macro-category. Interactive dressings can also be understood as “bioactive”: by managing exudate, they are able to reduce the inammatory process and regulate the concentration of factors involved in the repair process (cytokines, growth factors, and enzymes). Calcium alginate, for example, in contact with wound uids determines a dual action: the release of Ca++, which acts as a cofac­tor in the cascade of events that determines the activation of coagulation factor X; the absorption
of exudate operated by the bers that make up its structure, which, acting as a scaffold, promote the migration of broblasts and keratinocytes (Table23.1).
Interactive dressings can be used as a substrate for bioactive agents allowing for increasingly tar­geted action that takes into consideration the con­dition of the ulcer and the unique needs for restoration of skin integrity.
Common characteristics of all bioactive dress­ings are as follows:
• Generate a moist microenvironment.
• Facilitate the restoration of normal pH
values.
• Oxygen permeability.
• Ensure optimal oxygen concentration in the
ulcer bed.
• Ensure proper uid management.
• Biodegradability.
• Biocompatibility.
• Antioxidant action.
• They often require secondary dressing.
Schematically, BDs can be divided into two subgroups [3]:
F. D’Andrea (*) · F. Mosella Department of General Surgery, University of Naples “Federico II”, Naples, Italy e-mail: francesco.dandrea2@unina.it
© 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_23
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Table 23.1 shows the main characteristics of the different dressings [2]
Types of wound dressings Advantages Disadvantages Highlights
Nanobers They possess a structure that
mimics ECM, making them suitable for skin wound healing and regeneration. They are frequently formulated using efcient and easily employed electrospinning techniques.
Films and membranes
Hydrogels They are used as potential drug
Foams and wafers
Sponges and bandages
These wound dressings are transparent, showing that the wound-healing process can be observed without removing them. They also display good mechanical performance
delivery systems in wound dressing applications and display other interesting properties such as high porosity, high swelling capacity, excellent biocompatibility, etc.
These wound dressings exhibit high porosity that could provide cell growth and adhesion to accelerate the wound-healing process
These wound dressings also displayed high porosity that could offer suitable gaseous permeation, superior cell proliferation, migration, and attachment for accelerated wound-healing process.
It is not easy to produce nanobers less than 10nm in diameter
They are not suitable for exuding wounds due to their inability to absorb a large volume of biological uids.
The biopolymer hydrogel dressings demonstrate poor mechanical performance that makes them not compatible with human skin
They are not suitable for dry wounds
The very high porosity of the polymeric sponges or bandages can result in high uptake of wound exudate and high WVTR that may cause wound dehydration
The SEM micrographs of nanobers loaded with bioactive agents display bead-free morphology that mimics ECM, making these wound dressings appropriate for providing an environment for cell proliferation and adhesion to accelerate the diabetic wound-healing process
The mechanical properties of lms and membranes were like those of human skin, making them skin compatible and easily management during diabetic wound management
The drug release proles were controlled release of bioactive agents from the polymeric hydrogels, resulting in an improved wound-healing process. The high porosity of the hydrogels led to good swelling capability
The WVTR experiments of foams and wafers loaded with drugs exhibited moderate WVTR that can provide appropriate moisture to accelerate the healing of diabetic wounds
Polymeric sponges and bandages were mostly loaded with antibacterial agents for diabetic wound treatment, and they exhibited excellent antibacterial activity demonstrating that these dressings are potential candidates for the management of infected diabetic wounds
F. D’Andrea and F. Mosella
23.2 Bioactive
23.2.1 Bioactive Dressings
• Collagen
• Hyaluronic acid
• Alginates
• Chitin
• Chitosan
• Honey
• PHMB- enriched polymers
• Carbon dressings
23.2.2 Drug-releasing dressings
• Silver
• Iodopovidone
• Ozonides
• Mesoglycan
• DNA and ribosomes
• Rigenase
• MMP inhibitors
• Antibiotics
• Lidocaine
• Ibuprofen
• Biological components (GF, mesenchymal
cells, human-derived platelet lysates)
23 Bioinductive Dressing
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217
23.3 Drug-Loaded Wound Dressing
This already long list is bound to grow richer, given rapid technological advances. As is evident, the dividing line between advanced dressings and regenerative medicine is destined to become pro­gressively thinner. Scholars engaged in the study of Tissue Engineering, with the study of biomate­rials (sponges, lms, hydrogels, electrospun membranes, etc.) seek to overcome the limitations that are often obvious in the healing process with the goal of developing “the ideal dressing” that can meet specic requirements such as:
• provide/ensure a moist environment at the
wound site;
• enhance epidermal migration by promoting
angiogenesis and connective tissue synthesis;
• allow gas and nutrient exchanges;
• provide protection against bacterial infection;
and,
• must be sterilizable, nontoxic, biodegradable,
and hypoallergenic.
23.3.2 Biosynthesis andDegradation
Fibroblasts are the main source of collagen. After transcription, nascent/pre-pro-collagen is post­translationally modied in the endoplasmic reticu­lum into pro-collagen by removal of the signal peptide on the N-terminus. Hydroxylation and gly­cosylation of amino acid residues lead to the for­mation of the triple helical structure characteristic of collagens. Supported by chaperone proteins, the triple helical structure of pro-collagen is stabilized for further processing and maturation in the Golgi apparatus and assembled into secretory vesicles that are extruded into the extracellular space, where pro-collagen is enzymatically modied into tropo­collagen. The nal assembly of collagen brils occurs by covalent cross-linking. (Fig.23.1).
23.3.1 Collagen
Collagen is the most abundant protein in the extra­cellular matrix of the human body. Produced by broblasts, it is transformed to constitute complex morphologies [4, 5]. After initial and random depo- sition in the constitution of granulation tissue, the enzyme lysyl oxidase determines covalent bonds that allow its cross-linking. The type, amount, and organization of collagen vary in the healing wound and determine the tensile strength of the healed skin. Collagen III is synthesized in the early stages of healing, which is later replaced by collagen I, the most represented skin collagen. It plays a key role in the stages of wound healing due to its chemotac­tic effect on macrophages and broblasts, the cells most represented in the inammation, prolifera­tion, and maturation stages of wounds [6].
There are 28 different types of collagen, divided into brillar and non-brillar. Those most represented in the skin are type I, II, and V among brillar ones and type IV and XVIII among non­brillar ones [7, 8].
Fig. 23.1 Takashi Taguchi, M Shawkat Razzaque: The collagen-specic molecular chaperone HSP47: is there a role in brosis? Trends Mol Med. 2007 Feb;13(2):45–53 [9]
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