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TIMP1*
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F. D’Andrea and F. Mosella
action in two ways: by preventing the activation
of proenzyme molecules or by blocking the activity of activated MMPs [90] The presence of
bacteria in wounds can increase protease activity.
Bacteria induce an inammatory response that
stimulates protease production. In addition, the
bacteria themselves may produce the proteases
[91].
In healthy skin, the levels of MMPs are very
low. Under physiological conditions, following
injury, there is a rapid increase in proteases that
induces degradation of the damaged ECM and
assists in neutrophil recruitment and clearance of
any foreign bodies. The peak concentration
decreases within 5days leading quickly to restitutio ad integrum. In hard-to-heal wounds, persistence of high levels of proteases responsible
for growth factor degradation and prevalence of
ECM destruction processes over deposition processes are often observed. Such conditions fur-
Fig. 23.12 Schematic
representation of MMP
activation under inammatory
and wounding conditions. (a)
Overview of the production,
activation, and inhibition of
MMPs by TIMPs. (b)
Modulation of MMPs/TIMPs
production by reactive
oxygen species, other
proteases, and by cytokines
and growth factors released
under inammatory and
wounding conditions. These
regulations are reported in the
literature and may depend on
cell types and tissue
microenvironment [92]
b
Inflammatory cells
Inflammatory cells
Reactive oxygen species
ther fuel the inammatory response and the
release of harmful reactive oxygen species
(Cullen’s circle) leading to the blockage of healing in the inammatory phase.
Pro-MMPs are the inactive forms of MMPs;
MT-MMPs are membrane-type MMPs; TIMPs,
tissue inhibitor of metalloproteinases. The thin
curved arrow indicates activation of MMPs and
inhibition of MMPs.
Increased levels of MMPs do not result in
characteristic clinical signs that would diagnose
such an alteration. Such a condition may be
hypothesized when, despite good control of the
patient’s comorbidities and appropriate local
management (debridement of LOS, control of
bacterial load, good management of examination), the lesions appear to be in a stalled phase
(Figs.23.12 and 23.13).
To date, there is still no precise denition of
dressings that act on metalloproteases.
Wounded cells
Other Proteases
Serine proteases. or
other MMPs
MT-MMP
Wounded cells
MMPs
Pro-MMPs
TIMPs
Proteases
Cytokines and growth factor
MMPs
TIMPs
IL6, IL4,
TNF, TGF
β
MMPs
TIMPs TIMP-1 and TIMP-3 TIMP2,
MMP1#MMP3
MMP7, MMP11#MMP9,
MMP14#MMP17, MMP19,
MMP25
CTGF, HGF*
MMP2#MMP3
MMP9, MMP13,
MMP14,
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Fig. 23.13 Stalled wound characteristics [93]
239
Dissemond in the 2020 review (rst MMPs
biblio) distinguished dressings active on MMPs
into:
dressings that inhibit MMPs,
dressings that modulate MMPs.
The distinction between the two classes is
that the former were specically marketed for
their action on proteases, the latter result in
their modulation by rebalancing the ulcer
microenvironment.
The dressings that inhibit the secretion of
metalloproteases are essentially two:
Oxidized regenerated cellulose (ORC)/collagen commercialized in the late 1990s.
Lipid-Collagen Technology with
NanoOligosaccharide Factor (TLC-NOSF) introduced to the market in 2000.
ORC/collagen matrix is a sterile lyophilized
pad composed of 55% collagen and 45% oxidized regenerated cellulose (ORC). It reduces the
activity of elastase, MMPs (drastically collagenase and gelatinase), and oxygen free radicals.
Interacting with the injury, it inhibits tissue
degradation and promotes granulation tissue synthesis by inducing [94]:
• the reduction of proteolytic activity and free
radical damage,
• the binding and stabilization of growth factors
(PDGF),
• the increased recruitment of macrophages and
broblasts,
• the proliferation of broblasts [95].
It is a highly conformable dressing that
degrades on contact with exudate.
In wounds with little exudate, it can be activated with a few drops of distilled water or saline.
It is indicated in cleansed wounds with mild/
moderate exudation, both acute and chronic.
The timing of dressing changes should be
evaluated according to the characteristics of the
treated wound: It should not be removed until
complete breakdown.
Formulation with silver (ionically bonded to
regenerated cellulose) may be useful in cases of
240
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F. D’Andrea and F. Mosella
critical colonization or reduced immunologic
potential of the host.
Requires secondary dressing. Can be placed
under compression bandaging.
Lipid-colloid technology dressings with
NanoOligosaccharide Factor (TLC-NOSF) are a
range of dressings composed of carboxymethylcellulose particles distributed in a vaseline network and impregnated with NOSF on a
non-occlusive, soft, non-woven polyester layer
[96]. Upon contact with the exudate, the hydrocolloid particles form a gel that interacts with the
vaseline to form a lipidocolloid lm that creates a
moist environment within the wound. This results
in a kind of microadhesiveness of the dressings
that allows control of the ulcer microenvironment
and, at the same time, a reduction in discomfort
upon removal of the dressing.
Potassium salt of sulfated oligosaccharides
[97] is able to enhance and speed up the reparative process by determining the inhibition of
MMPs, interaction with growth factors, and restoration of their biological functions. In vitro
studies on an equivalent dermal model have
shown that TLC-NOSF is able to signicantly
reduce the activity of some MMPs, such as gelatinases (MMP2 and MMP9) and collagenases
(MMP1 and MMP8) present in exudate [98, 99].
TLC-NOSF dressings can be distinguished
into.
Simple: polyester weft impregnated with a
colloidal lipid matrix rich in saccharide factors.
Interactive: composed entirely of polyacrylateabsorbent bers, detergents, and gelling agents
and a TLC-NOSF matrix. It is also marketed in
edged form with silicone adhesive margins.
With the exception of the edged dressing, they
all require secondary dressing.
The choice of type is based primarily on the
level of exudation.
They can remain in place for up to seven days.
Use is indicated in cleansed lesions, both
acute and chronic. It is noteworthy that the TLCNOSF matrix: is the only treatment recommended by Nice (UK) for the management of
patients with venous lesions of the lower extremities and diabetic foot; it has been included in the
2019 guidelines compiled by the International
Working Group on the Diabetic Foot the best
standard of care in noninfected neuropathic diabetic ulcers [100].
They require secondary dressing. They can be
placed under bandages.
There are numerous devices placed on the
market that, by regulating the characteristics of
the ulcer bed (ES pH), exert a reduction in the
levels of MMPs. These may include modulators
of the pH of the wound environment through an
ion exchange mechanism, acetate mesh media
containing potassium chloride, rubidium chloride, calcium chloride, zinc chloride, potassium
citrate, and citric acid.
References
1. Schoukens G.Bioactive dressings to promote wound
healing. Sawston: Woodhead Publishing; 2019.
2. Alven S, Peter S, Mbese Z, Aderibigbe BA.Polymerbased wound dressing materials loaded with bioactive agents: potential materials for the treatment of
diabetic wounds. Polymers. 2022;14:724. https://doi.
org/10.3390/polym14040724.
3. Laurano R, Bofto M, Ciardelli G, Chiono V.Wound
dressing products: a translational investigation from
the bench to the market. Eng Regen. 2022;3:182–200.
4. Reilly DM, Lozano J.Skin collagen through the life
stages: importance for skin health and beauty. Plast
Aesthetic Res. 2021;8:2.
5. Ricard-Blum S. The collagen family. Cold Spring
Harb Perspect Biol. 2011;3:a004978.
6. Mathew-Steiner SS, Roy S, Sen CK. Collagen in
wound healing. Bioengineering. 2021;8:63. https://
doi.org/10.3390/bioengineering8050063.
7. Onursal C, Dick E, Angelidis I, Schiller HB, StaabWeijnitz CA.Collagen biosynthesis, processing, and
maturation in lung ageing. Front Med. 2021;8:593874.
https://doi.org/10.3389/fmed.2021.593874.
8. Sorushanova A, Delgado LM, Wu Z, Shologu N,
Kshirsagar A, Raghunath R, Mullen AM, Bayon
Y, Pandit A, Raghunath M, et al. The collagen
Suprafamily: from biosynthesis to advanced biomaterial development. Adv Mater. 2019;31:1801651.
9. Taguchi T, Razzaque MS. The collagen-specic
molecular chaperone HSP47: is there a role in brosis? Trends Mol Med. 2007;13(2):45–53.
10. San Antonio JD, Jacenko O, Fertala A, Orgel
J.Collagen structure-function mapping informs applications for regenerative medicine. Bioengineering.
2020;8:3.
11. Govindaraju P, Todd L, Shetye S, Monslow J, Puré
E. CD44-dependent inammation, brogenesis, and
collagenolysis regulates extracellular matrix remodel-
23 Bioinductive Dressing
https://t.me/medicina_free
241
ing and tensile strength during cutaneous wound healing. Matrix Biol. 2019;75–76:314–30.
12. Pallaske F, Pallaske A, Herklotz K, BoeseLandgraf J. The signicance of collagen dressings
in wound management: a review. J Wound Care.
2018;27(10):692–702.
13. Amirrah IN, Farhanulhakim M, Razip M, Tabata Y,
Bt R, Idrus H, Nordin A, Fauzi MB.Antibacterialintegrated collagen Wound dressing for diabetesrelated foot ulcers: an evidence-based review of
clinical studies. Polymers. 2020;12:2168.
14. Gaspar-pintiliescu A, Stanciuc A, Craciunescu
O. Natural composite dressings based on collagen,
gelatin and plant bioactive compounds for wound healing: a review. Int J Biol Macromol. 2019;138:854–65.
15. Furlan D, Bonfanti G, Scappaticci G. Non-porous
collagen sheet for therapeutic use, and the method
and apparatus for preparing it. US Patent. #5785983.
1993.
16. Wahab N, Roman M, Chakravarthy D, Luttrell T.The
use of a pure native collagen dressing for wound bed
preparation prior to use of a living bi-layered skin
substitute. J Am Coll Clin Wound Spec. 2015;6:2–8.
17. Elgharably H, Roy S, Khanna S, Abas M, DasGhatak
P, Das A, Mohammed K, Sen CK.A modied collagen gel enhances healing outcome in a preclinical
swine model of excisional wounds. Wound Repair
Regen. 2013;21:473–81.
18. Watt PW, Harvey W, Wiseman D, Light N, Saferstein
L, Cini J.Wound dressing materials comprising collagen and oxidized cellulose. European Patent. EP
1325754 B1.
19. DiTizio V, DiCosmo F, Xiao Y.Non-adhesive elastic
gelatin matrices. US Patent. US 8,628,800 B2. 2014.
20. Mbese Z, Alven S, Aderibigbe BA.Collagen-based
nanobers for skin regeneration and wound dressing
applications. Polymers. 2021;13:4368.
21. Tavianatou AG, Caon I, Franchi M, Piperigkou
Z, Galesso D, Karamanos NK. Hyaluronan:
molecular size-dependent signaling and biological functions in inammation and cancer. FEBS J.
2019;286(15):2883–908. https://doi.org/10.1111/
febs.14777. Epub 2019 Feb 21.
22. Bohaumilitzky L, Huber A-K, Stork EM, Wengert
S, Woel F, Boehm H. A trickster in disguise:
Hyaluronan's ambivalent roles in the Matrix.
Front Oncol. 2017;7:242. https://doi.org/10.3389/
fonc.2017.00242. eCollection 2017.
23. Kouvidi K, Berdiaki A, Nikitovic D, Katonis P, Afratis
N, Hascall VC, Karamanos NK, Tzanakakis GN.Role
of receptor for hyaluronic acid-mediated motility
(RHAMM) in Low Molecular Weight Hyaluronan
(LMWHA)-mediated brosarcoma cell adhesion. J
Biol Chem. 2011;286(44):38509–20.
24. Yang C, Cao M, Liu H, He Y, Xu J, Du Y, Liu Y, Wang
W, Cui L, Hu J, Gao F.The high and low Molecular
weight forms of Hyaluronan have distinct effects on
CD44 clustering. J Biol Chem. 2012;287(51):43094–
107. https://doi.org/10.1074/jbc.M112.349209.
25. Graça MFP, Miguela SP, Cabrala CSD, Correia
IJ. Hyaluronic acid—based wound dressings: a
review. Carbohydr Polym. 2020;241:116364. https://
doi.org/10.1016/j.carbpol.2020.116364.
26. Baldino L, Cardea S, Reverchon E.Optimization of
hyaff membranes morphology produced by supercritical phase separation for biomedical applications. Chem Eng Trans. 2017;57:1333–8. https://doi.
org/10.3303/CET1757223.
27. Rossi M, Marrazzo P. The potential of honeybee
products for biomaterial applications. Biomimetics.
2021;6:6.
28. Combarros-Fuertes P, Fresno JM, Estevinho MM,
Sousa-Pimenta M, Tornadijo ME, Estevinho
LM. Honey: another alternative in the ght against
antibiotic-resistant bacteria? Antibiotics. 2020;9:774.
29. Campeau MEM, Patel R. Antibiolm activity of
Manuka honey in combination with antibiotics. Int J
Bacteriol. 2014;2014:795281.
30. Maddocks SE, Jenkins RE.Honey: a sweet solution
to the growing problem of antimicrobial resistance?
Future Microbiol. 2013;8:1419–29.
31. Silvia PMD, Gauche C, Gonzaga LV, Costa ACO,
Fett R. Honey: chemical composition, stability and
authenticity. Food Chem. 2016;196:309–23.
32. Combarros-Fuertes P, Valencia-Barrera RM,
Estevinho LM, Dias LG, Castro JM, Tornadijo ME,
Fresno JM.Spanish honeys with quality brand: a multivariate approach to physicochemical parameters,
microbiological quality, and oral origin. J Apic Res.
2019;58:92–103.
33. Hixon KR, Klein RC, Eberlin CT, Linder HR, Ona
WJ, Gonzalez H, Sell SA.A critical review and perspective of honey in tissue engineering and clinical
wound healing. Adv Wound Care. 2019;8:403–15.
34. Molan PC. Honey: antimicrobial actions and role in
disease management. In: New strategies combating
bacterial infection. Weinheim: Wiley; 2009. p. 229–
53. ISBN 9783527322060.
35. Krishnakumar GS, Mahendiran B, Gopalakrishnan S,
Muthusamy S, Malarkodi Elangovan S.Honey based
treatment strategies for infected wounds and burns:
a systematic review of recent pre-clinical research.
Wound Med. 2020;30:100188.
36. Cooper R, Jenkins L, Rowlands R.Inhibition of biolms through the use of Manuka honey. Wounds.
2011;7:24–32.
37. Merckoll P, Jonassen TØ, Vad ME, Jeansson SL,
Melby KK. Bacteria, biolm and honey: a study of
the effects of honey on “planktonic” and biolmembedded chronic Wound bacteria. Scand J Infect
Dis. 2009;41:341–7.
38. Jenkins R, Cooper R. Improving antibiotic activity against Wound pathogens with Manuka honey
invitro. PLoS One. 2012;7:e45600.
39. Scepankova H, Combarros-Fuertes P, Fresno JM,
Tornadijo ME, Dias MS, Pinto CA, Saraiva JA,
Estevinho LM. Role of honey in advanced Wound
care. Molecules. 2021;26:4784.
242
https://t.me/medicina_free
F. D’Andrea and F. Mosella
40. Brudzynski K, Miotto D. The relationship between
the content of Maillard reaction-like products
and Bioactivity of Canadian honeys. Food Chem.
2011;124:869–74.
41. Stewart JA, McGrane OL, Wedmore IS. Wound
Care in the Wilderness: is there evidence for honey?
Wilderness Environ Med. 2014;25:103–10.
42. Eteraf-Oskouei T, Naja M, Gharehbagheri
A.Natural honey: a new and potent anti-Angiogenic
agent in the air-pouch model of inammation. Drug
Res. 2013;64:530–6.
43. Barui A, Mandal N, Majumder S, Das RK, Sengupta
S, Banerjee P, Ray AK, Roychaudhuri C, Chatterjee
J.Assessment of Molecular events during invitro reepithelialization under honey-alginate Matrix ambience. Mater Sci Eng C. 2013;33:3418–25.
44. Manisha Deb Mandal. Shyamapada Mandal: honey:
its medicinal property and antibacterial activity. Asian
Pac J Trop Biomed. 2011;1(2):154–60.
45. Annapoorani A, Anilakumar KR, Khanum F, Murthy
NA, Bawa AS.Studies on the physicochemical characteristics of heated honey, honey mixed with ghee
and their food consumption pattern by rats. Ayu.
2010;31(2):141–6.
46. Molan P, Rhodes T.Honey: a biologic Wound dressing. Wounds. 2015;27:141–51. [PubMed].
47. Wayne RP. Chemistry of atmospheres. Oxford:
Oxford Science; 1991. Chimica ambientale, Colin
Baird e Michael Cann. Terza edizione italiana condotta sulla quinta edizione americana. A cura di Eudes
Lanciotti e Massimo Stefani.Brugherio. Edizione
Zanichelli. 2013.
48. Ministero della Salute. Direzione generale della prevenzione sanitaria. Direzione generale della comunicazione e dei rapporti europei e internazionali: ozono.
2015. https://www.salute.gov.it/imgs/C_17_opusco-
liPoster_283_ulterioriallegati_ulterioreallegato_8_
alleg.pdf.
49. Bocci V. Ozone: a new medical drug. Holanda:
Springer; 2005.
50. Schwartz A, Sánchez GM, Sabah F. Madrid declaration on ozone therapy. Madrid: International Scientic
Committee of Ozone Therapy; 2015.
51. Anzolin AP, da Silveira-Kaross NL, Bertol
CD.Ozonated oil in wound healing: what has already
been proven? Med Gas Res. 2020;10(1):54–9.
https://doi.org/10.4103/2045- 9912.279985. PMID:
32189671; PMCID: PMC7871935.
52. Sadowska J, Johansson B, Johannessen E, Friman R,
Broniarz-Press L, Rosenholm JB. Characterization
of ozonated vegetable oils by spectroscopic and
chromatographic methods. Chem Phys Lipids.
2008;151:85–91.
53. Marmo E.Farmacologia generale e speciale. Torino:
UTET; 1991. p.146.
54. Bocci V, Zanardi I, Travagli V. Oxygen/ozone as a
medical gas mixture. A critical evaluation of the various methods claries positive and negative aspects.
Med Gas Res. 2011;1:6.
55. Cardoso CC, Dias Filho E, Pichara NL, Campos
EGC, Pereira MA, Fiorini JE. Ozonoterapia como
tratamento adjuvante na ferida de pé diabético. Rev
Assoc Med Minas Gerais. 2010;20:442–5.
56. Shi D, Sheng A, Chi L.Glycosaminoglycan-Protein
interactions and their roles in human disease. Front
Mol Biosci. 2021;8:639666. https://doi.org/10.3389/
fmolb.2021.639666.
57. da Voet DC, Pratt W, Voet JG, Fondamenti di
Biochimica. Zanichelli editore spa. 2013.
58. Sodhi H, Panitch A. Glycosaminoglycans in Tissue
Engineering: A Review. Biomolecules. 2020;
11(1):29. https://doi.org/10.3390/biom11010029.
PMID: 33383795; PMCID: PMC7823287.
59. Melrose. Glycosaminoglycans in wound healing.
Bone Tissue Regener Insights. 2016;7:29–50. https://
doi.org/10.4137/BTRI.S38670.
60. Arosio E, Ferrari G, Santoro L, Gianese F, Coccheri
S, Mesoglycan Venous Insufciency Group. A
placebo-controlled, double-blind study of mesoglycan in the treatment of chronic venous ulcers. Eur J
Vasc Endovasc Surg. 2001;22:365–72. https://doi.
org/10.1053/ejvs.2001.1478.
61. Tufano A, Arturo C, Cimino E, Di Minno MN,
DiCapua M, Cerbone AM, Di Minno G.Mesoglycan:
clinical evidences for use in vascular diseases.
Int J Vasc Med. 2010;2010:390643. https://doi.
org/10.1155/2010/390643.
62. Belvederea R, Valentina Bizzarro A, Parentea L,
Petrella F, Petrella A.Effects of Prisma Skin dermal
regeneration device containing glycosaminoglycans
on human keratinocytes and broblasts. Cell Adh
Migr. 2018;12(2):168–83. https://doi.org/10.1080/19
336918.2017.1340137.
63. Bizzarro V, Belvedere R, Pessolano E, Parente L,
Petrella F, Perretti M, Petrella A.Mesoglycan induces
keratinocyte activation by triggering syndecan-4 pathway and the formation of the annexin A1/S100A11
complex. J Cell Physiol. 2019;234(11):20174–92.
https://doi.org/10.1002/jcp.28618.
64. Petrella F, Belvedere R, Labbro V, Apicella A, Bizzarro
V, Pessolano E, Parente L, Petrella A. A new pharmaceutical device containing mesoglycan modulates
broblasts function in vivo. Pharmacologyonline.
2020;1:20–30.
65. Belvedere R, Bizzarro V, Parente L, Petrella F,
Petrella A.The Pharmaceutical device Prisma® skin
promotes invitro angiogenesis through endothelial to
mesenchymal transition during skin Wound Healing.
Int J Mol Sci. 2017;25(18):pii: E1614. https://doi.
org/10.3390/ijms18081614.
66. Squadrito F, Bitto A, Irrera N, Pizzino G, Pallio G,
Minutoli L, Altavilla D.Pharmacological activity and
clinical use of PDRN.Front Pharmacol. 2017;8:224.
https://doi.org/10.3389/fphar.2017.00224.
67. Galeano M, Pallio G, Irrera N, Mannino F, Bitto
A, Altavilla D, Vaccaro M, Squadrito G, Arcoraci
V, Colonna MR, et al. Polydeoxyribonucleotide:
a promising biological platform to accelerate
23 Bioinductive Dressing
https://t.me/medicina_free
243
impaired skin wound healing. Pharmaceuticals
(Basel). 2021;14(11):1103. https://doi.org/10.3390/
ph14111103. PMID: 34832885; PMCID:
PMC8618295.
68. Chavan AJ, Haley BE, Volkin DB, Mara KE,
Verticelli AM, Bruner MW, Draper JP, Burke CJ,
Middaugh CR.Interaction of nucleotides with acidic
broblast growth factor (FGF-1). Biochemistry.
1994;33:7193–202.
69. Thellung S, Florio T, Maragliano A, Cattarini G,
Schettini G. Polydeoxyribonucleotides enhance the
proliferation of human skin broblasts: involvement of A2 purinergic receptor subtypes. Life
Sci. 1999;64:1661–74. https://doi.org/10.1016/
S0024- 3205(99)00104- 6.
70. Jing X, Sun Y, Liu Y, Ma X, Hao H.Alginate/chitosanbased hydrogel loaded with gene vectors to deliver
polydeoxyribonucleotide for effective wound healing.
Biomater Sci. 2021;9:5533.
71. Squadrito F, Bitto A, Altavilla D, Arcoraci V, De
Caridi G, De Feo ME, Corrao S, Pallio G, Sterrantino
C, Minutoli L, Saitta A, Vaccaro M, Cucinotta D.The
effect of PDRN, an adenosine receptor A2A agonist, on the healing of chronic diabetic foot ulcers:
results of a clinical trial. J Clin Endocrinol Metab.
2014;99(5):E746–53. https://doi.org/10.1210/
jc.2013- 3569. Epub 2014 Jan 31. Erratum in: J Clin
Endocrinol Metab. 2015 Feb;100(2):763. PMID:
24483158.
72. Valdatta L, Thione A, Mortarino C, Buoro M,
Tuinder S. Evaluation of the efcacy of polydeoxyribonucleotides in the healing process of
autologous skin graft donor sites: a pilot study.
Curr Med Res Opin. 2004;20:403–8. https://doi.
org/10.1185/030079904125003116.
73. Polito F, Bitto A, Galeano M, Irrera N, Marini H, Cal
M, etal. Polydeoxyribonucleotide restores blood ow
in an experimental model of ischemic skin aps. J
Vasc Surg. 2012;55:479–88. https://doi.org/10.1016/j.
jvs.2011.07.083.
74. Chung KI, Kim HK, Kim WS, Bae TH.The effects
of polydeoxyribonucleotide on the survival of random
pattern skin aps in rats. Arch Plast Surg. 2013;40:181–
6. https://doi.org/10.5999/aps.2013.40.3.181.
75. Cuomo O, et al. Oligosaccharidic fractions derived
from Triticum vulgare extract accelerate tissutal
repairing processes in invitro and in vivo models of
skin lesions. J Ethnopharmacol. 2015;158:198.
76. Cuomo O, et al. Triticum vulgare extract exerts
an antiinammatory action in two in vitro models of inammation in microglial cells. Plos One.
2018;14:e0197493.
77. Romanelli M, et al. Triticum vulgare extract modulates protein-kinase B and matrix metalloproteinases 9 protein expression in BV-2 cells: bioactivity
on inammatory pathway associated with molecular mechanism wound healing. Mediat Inamm.
2020;2020:1.
78. Limauro D, etal. Antioxidant capacity of Rigenase®,
a specic aqueous extract of Triticum vulgare.
Antioxidants. 2018;7:67.
79. Tito, etal. A Triticum vulgare extract exhibits regenerating activity during the wound healing process.
Clin Cosmet Investig Dermatol. 2020;13:21.
80. Schiraldi C, etal. Molecular mechanisms at the basis
of pharmaceutical grade Triticum vulgare extract efcacy in prompting keratinocytes healing. Molecules.
2020;25(3):431.
81. Martini P, et al. Efcacy and tolerability of
Fitostimoline® in two different forms (soaked gauzes
and cream) and Ci-trizan Gel in the topical treatment of second-degree supercial cutaneous burns.
Dermatol Res Pract. 2011;2011:978291.
82. Silvestrini S, WUWHS. The fundamental role of
bioactive medications based on Rigenase® (aqueous
extract of Triticum Vulgare) and Phenoxitanol in the
treatment of pressure injuries, dehiscences of surgical wounds, rst and second degree burns, abrasions,
breast ssures secondary to lactation, anal ssures—
an observational study. 2020
83. Dissemond J, Augustin M, Dietlein M, Faust U,
Keuthage W, Lobmann R, Münter KC, Strohal R,
Stücker M, Traber J, Vanscheidt W, Läuchli S.Efcacy
of MMP-inhibiting wound dressings in the treatment
of chronic wounds: a systematic review. J Wound
Care. 2020;29(2):102–18. https://doi.org/10.12968/
jowc.2020.29.2.102. PMID: 32058850.
84. Lenci E, Cosottini L, Trabocchi A. Novel matrix
metalloproteinase inhibitors: an updated patent review (2014–2020). Expert Opin Ther Pat.
2021;31:509.
85. Dissemond J, Dowsett C, Schultz G, Serena T.EPA
made easy. Wounds Int. 2013;4:1.
86. Cullen B, Smith R, McCullock E, et al. Mechanism
of action of PROMOGRAN®, a protease modulating matrix, for the treatment of diabetic foot ulcers.
Wound Repair Regen. 2002;10:16–25.
87. Lee WL, Downey GP. Leukocyte elastase.
Physiological functions and role in acute lung injury.
Am J Repir Crit Care Med. 2001;164:896–904.
88. Löffek S, Schilling O, Franzke CW. Series “matrix
metalloproteinases in lung health and disease”: biological role of matrix metalloproteinases: a critical
balance. Eur Respir J. 2011;38(1):191–208. https://
doi.org/10.1183/09031936.00146510. Epub 2010
Dec 22. PMID: 21177845.
89. Loffek S, Schilling O, Franzke C-W. Biological
role of matrix metalloproteinases: a critical balance. Eur Respir J. 2011;38:191–208. https://doi.
org/10.1183/09031936.00146510.
90. Rai RR, Phadke MS. Plasma antiprotease status
indifferent respiratory disorders. Int J Pulmon Med.
2007;7(1):1. https://doi.org/10.5580/1d0.
91. Alameddinea HS, Morganb JE. Matrix metalloproteinases and tissue inhibitor of metalloproteinases
review. J Neuromusc Dis. 2016;3:455–73.
92. McCarty SM, Cochrane CA, Clegg PD, Percival
SL.The role of endogenous and exogenous enzymes
in chronic wounds: a focus on the implications
of aberrant levels of both host and bacterial proteases in wound healing. Wound Repair Regen.
2012;20(2):125–36.
244
https://t.me/medicina_free
F. D’Andrea and F. Mosella
93. Widgerow AD. Deconstructing the stalled wound
review. Wounds. 2012;24(3):58–66.
94. Loh ML, Goh BKL, Kong Y, etal. Combination therapy of oxidised regenerated cellulose/collagen/silver
dressings with negative pressure wound therapy for
coverage of exposed critical structures in complex
lower extremity wounds. Int Wound J. 2020;17:1356–
65. https://doi.org/10.1111/iwj.13406.
95. Cullen B, Watt PW, Lundqvist C, et al. The role of
oxidised regenerated cellulose/collagen in chronic
wound repair and its potential mechanism of action.
Int J Biochem Cell Biol. 2002;34(12):1544–56.
96. Richard JL, Martini J, Bonello Faraill MM, Bemba
JM, Lepeut M, Truchetet F, Ehrler S, Schuldiner S,
Sauvadet A, Bohbot S.Management of diabetic foot
ulcers with a TLC-NOSF wound dressing. J Wound
Care. 2012;21(3):142–7. https://doi.org/10.12968/
jowc.2012.21.3.142. PMID: 22399083.
97. Lázaro-Martínez JL, Edmonds M, Rayman G,
Apelqvist J, Van Acker K, Hartemann A, Martini
J, Lobmann R, Bohbot S, Kerihuel JC, Piaggesi
A.Optimal wound closure of diabetic foot ulcers with
early initiation of TLC-NOSF treatment: post-hoc
analysis of explorer. J Wound Care. 2019;28(6):358–
67. https://doi.org/10.12968/jowc.2019.28.6.358.
PMID: 31166858.
98. Schmutz JL, Meaume S, Fays S, Ourabah Z,
Guillot B, Thirion V, Collier M, Barrett S, Smith J,
Bohbot S, Dompmartin A.Evaluationof the nanooligosaccharide factor lipido-colloid matrix in the
local management of venous leg ulcers: results
of a randomised, controlled trial. Int Wound J.
2008;5:172–82.
99. Coulomb B, Couty L, Fournier B, etal. Evaluation
of the matrix impregnated with NOSF (Nano oligo
saccharide factor) in an invitro dermal reconstruction model. JPC. 2008;63(8):54–7.
100. Nair H, Venkateshwaran N, Seetharaman SS,
Deng W, Uthaipaisanwong A, Galea E.Benets of
sucrose octasulfate (TLC-NOSF) dressings in the
treatment of chronic wounds: a systematic review.
J Wound Care. 2021;30(Sup4):S42–52. https://
doi.org/10.12968/jowc.2021.30.Sup4.S42. PMID:
33856929.
Skin Substitutes
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VitoCazzato, GraceMarchi,
MariaGiuliaSpazzapan, andGiovanniPapa
24
24.1 Introduction
The skin represents the largest external defense
system of the human body and protects the organism from the action of pathogenic agents. It is
made of three layers: the epidermis, the dermis,
and the subcutaneous tissue, and acts as physical
barrier against traumatic penetration. A vascular
system that provides the tissues with oxygen and
nutrients exists within the dermis that is made of
connective tissue, granting elasticity and mechanical resistance. The hypodermis, or subcutaneous
fat, is the deepest layer that provides both thermic
and mechanical protection.
When injured, an inammatory response with
deployment of immune cells is activated, with subsequent release of cytokines which play a key role
in re-epithelialization and cutaneous remodeling
processes. Precisely, during wound healing, broblasts’ activity is crucial for dermal repair. In primary-intention healing, they produce collagen and
extracellular matrix proteins that recreate, within
correct timing, an organized and well-cellularized
type of dermis. In the context of secondary-inten-
V. Cazzato · G. Marchi · G. Papa (*)
Plastic Surgery Unit, University of Trieste, Cattinara
Hospital, Trieste, Italy
e-mail: giovanni.papa@asugi.sanita.fvg.it
M. G. Spazzapan
Department of Molecular Biomedicine University of
Trieste, Trieste, Italy
e-mail: mariagiulia.spazzapan@phd.units.it
tion healing, broblasts’ hyperactivity forms a
brous and highly cellularized scar tissue via granulation tissue. Therefore, the newly formed scar
tissue does not allow complete functional repair,
leading to a skin with different characteristics. It is
easier that, in patients with comorbidities such as
hypovascularization, a deep wound is transformed
into chronic and re- epithelization can only take
place from the margins.
Large post-traumatic tissue loss has lead
researchers to develop new technologies to
improve wound coverage, with the aim of restoring the skin and all its functions. Injuries and
burn that reach the deep part of the dermis, or
further down beyond it, struggle to heal by secondary intention and become chronic wounds
only after a prolonged amount of time.
A reliable surgical solution has been found for
these conditions and consists of skin grafts: these
can be divided into full-thickness skin grafts
(FTSG) or split-thickness skin grafts (STSG), the
rst ones including the epidermis and the entire
dermis, the second ones including the epidermis
and only part of the dermis.
This surgical option, despite its versatility,
comes with several downsides such as donor site
pain, failed take of the graft, limited availability
of donor sites. These main reasons have encouraged researchers to consider surgical alternatives
for wound coverage, such as the use skin substitutes or bio-scaffolds to minimize donor site morbidity up to the preservation of autologous
© 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_24
245
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V. Cazzato et al.
tissues. Skin substitutes consist of biomaterials
developed to accelerate wound healing, providing extracellular matrix (ECM) substitutes [1].
Their role is to act as barrier against microorganisms, to minimize pain, encourage wound
healing, and help restore the protective function
of the skin. Moreover, their use leads to an
improvement of cutaneous regeneration (organized in consecutive phases), to a reduction of
scar contracture, and improves the quality and
the elasticity of the neodermis, along with reducing donor site morbidity.
Dermal substitutes have been largely utilized
to minimize the normal biological response
linked to myobroblast activity, such as wound
scar contracture. Nathoo etal. [2] have provided
a list of properties an “ideal cutaneous substitute”
should present:
– infection resistance
– lack of antigenicity
– sustainable costs
– wide availability
– simple application and removal
– stability and durability.
protection from liquid loss,
adaptability and exibility to the wound
bed’s characteristics [3],
restore functional and aesthetic properties
[4],
provide a stable and biodegradable scaffold
to promote development of new dermal
tissue.
allow the host cells to grow and proliferate
within the scaffold [5].
Despite constant progress in the development
of skin substitutes, to this day there is not a single
product that is considered to be the gold standard
for the treatment of wounds that require restoration of continuity and functionality.
Skin substitutes should have functional and
structural characteristics that equal those of
autologous skin. The ideal skin substitute would
be durable, entirely autologous incorporating
adnexal structures and adult stem cells. A product
with these characteristics, however, is yet to be
developed.
24.2 Characteristics
andComposition
Cellular migration within the matrix is a fundamental requirement for regenerative activity: the
latter is inuenced by the porosity of the substitute. The ideal pore diameter varies between 70
and 120nm.
Cutaneous substitutes are composed of a main
element, the scaffold, which interacts with cells
and growth factors [6, 7]. The scaffold inside the
dermal substitute represents and replicates the
extracellular matrix (ECM) and, as the latter,
consists of a tridimensional structure: its function
is to support adhesion, cellular proliferation, and
differentiation along with neo-vascularization
processes, which are essential for cellular survival. Cell-matrix interactions within the substitute are regulated by the presence of appropriate
ligands (alpha1beta1, alpha1beta2) that allow
cellular adhesion. Various polymers can be used
to create different scaffolds, and each of these
provides various diverse bio-chemical and physical properties [6, 7]. The presence of specic elements regulates the stability of the dermal
substitute in the body and its degradation time [8]
has proven that the presence of macromolecules
like chondroitin-6-sulfate stabilize the scaffold
improving its bonds with ECM cells, granting in
fact the permanence/slowness of the dermal substitute that can thus be invaded by non-cellular
components of the host organism. The lack of
macromolecules and the breakdown rapidity,
instead, allows to promote the formation of granulation tissue, preparing the wound bed for subsequent reconstructive surgery.
Three are the main types of biomaterials used
as scaffolds: natural, synthetic, and composite
(combination of natural and synthetic). Bearing
in mind that scaffolds are destined to carry similar characteristics to the ECMs of natural tissues,
for this reason natural biomaterials represent
ideal components and are therefore the most utilized for the production of scaffolds.
Biocompatible materials that are commonly used
in tissue engineering include collagen, gelatin,
elastin, hyaluronic acid (HA), brin/bronectin
[9]. Despite collagen being the main element,
24 Skin Substitutes
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247
most scaffolds gain different and specic invitro
characteristics according to which biomaterial is
added: in this way, it is also possible to predict
clinical effects of the different dermal
substitutes.
Various studies have focused on the possibility
of modifying collagen’s structure to allow the substitute to gain further characteristics: by adding
ECM proteins to type I collagen for instance, such
as tropoelastin, enhances broblasts’ proliferation
and migration rate in vitro [10]. Chitosan crosslinked collagen creates an optimal potential for the
migration of keratinocytes and re- epithelialization
of the wound [11]. The addition of broblast
growth factor 2 (FGF2) or vascular endothelial
growth factor (VEGF) to heparin reticulated collagen scaffold raises its angiogenic potential [12].
The different stability of the various biomaterials
allows substitutes to be divided into two big
groups: permanent (bio-conductor that allows dermal replacement and/or granulation tissue formation) and temporary (bio- inductors of granulation
tissue) which undergo breakdown and might need
to be renewed. This partitioning enables to easily
navigate the sea of classications and categorization currently available in this eld.
It is clear that in order to be permanent, a dermal substitute must have specic characteristics
such as no rejection reaction and/or biological
incompatibility. Particularly, analyzing histological samples of the neodermis obtained from the
dermal substitute (e.g., Integra), even after a veyear time it displays a well-dened and stable 3D
structure, with pronounced collagen and elastin
invasion and features more comparable to the
normal skin rather than to a skin graft [13]: this
gives an optimal structural support and a primary
healing. The best dermal substitute, reconstructing a well-organized neodermis, with a low
amount of cells and a proper balance between
collagene bers and ECM, supports a primary
healing, like for skin grafts or aps. On the contrary, bio-inductors are able to stimulate a rapid
inammatory response which, through a breakdown and production mechanism carried out by
macrophages and broblasts, leads to the rapid
formation of granulation tissue and a secondary
healing.
Classication of dermal substitutes divided
into dermo-conductive and dermo-inductive is
therefore supported by these principles. These
categories were originally introduced by Kim
et al. in 2007 [14]. Dermo-conductors, instead,
are products that supply a scaffold onto which
cells of the nearby tissues can migrate to reach
the wound and form the neodermis. Integra (LifeSciences, Plainsboro, NJ), GraftJackeTechnology, Arlington TN), Oasis (Smith & Nephew,
Memphis, TN), Alloderm (LifeCell, Branchburg,
NJ), and EZ Derm (Molnlycke, Gothenburg,
Sweden) are examples of these products
[15–17].
Dermo-inductors include products that provide the wound with cells that stimulate the activation of new growth factors or granulation
tissue. Example of such products available on the
market include Apligraf(Organogenesis, Canton,
MA), Dermagraft (Organogenesis, Canton, MA),
TheraSkin (Soluble Systems, LLC,
NewportNews, VA), Biobrane (Smith & Nephew,
Memphis, TN), and Epicel (Genzyme,
Cambridge, MA).
Nevertheless, these types of classications do
not consider the clinical aspect of the wound’s
healing process. Behavioral and structural properties of a permanent dermal substitute are
observed when the wound bed is suitable for
graft taking, may not be observed when placed
onto a wound bed that has not been properly prepared and shows contamination, presence of
brin, infection, or inammation.
In this case, the dermal substitute would not
adequately blend in with the host tissue.
Unsuitable host environments will lead to the
breakdown of the dermal substitute that for this
reason could only promote the formation of granulation tissue and a secondary healing.
It is clear what an important role the scaffold’s
biomaterials play in the context of dermal
substitutes.
Lets analyze in detail which scaffold biomaterials are most commonly used in tissue
engineering:
Collagen: it is considered the main source of
traction endurance of the skin [18, 19] and is the
most used biomaterial for the production of skin
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