Emerging Antimicrobial and Immunomodulatory Fiber-Based Scaffolding Systems for Treating Diabetic Foot Ulcers
Abstract
:1. Introduction
2. Diabetic Ulcers: Healing Impairments and Classifications
2.1. Impairments
2.2. Classification
- -
- Grade 1. Partial thickness involving only dermis and epidermis
- -
- Grade 2. Full thickness and subcutaneous tissues
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- Grade 3. Grade 2 plus exposed tendons, ligament, and/or joint
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- Grade 4. Grade 3 plus abscess and/or osteomyelitis
- -
- Grade 5. Grade 3 plus necrotic tissue in wound
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- Grade 6. Grade 3 plus gangrene in the wound and surrounding tissue
3. Antimicrobial Agents
3.1. Antibiotics
3.2. Natural Extracts
3.3. Inorganic Nanoparticles
3.4. Polymers: Chitosan
4. Immunomodulatory Agents
4.1. Growth Factors
4.2. Blood Components: Platelet-Rich Plasma
4.3. Natural Extracts
4.4. Proteins: Collagen, Silk Fibroin and Sericin, and Keratin
4.5. Neuropeptides
4.6. Stem Cells
4.7. Polymers: Alginate and Hyaluronic Acid
5. Advanced Fibrous Scaffolds
6. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Technique | Final System | Components | Main Bioactive Agents Categories | DFUs Care Potential | Ref. |
---|---|---|---|---|---|
Electrospinning | Triple Layer Mesh | Outer and middle layers: sodium alginate (SA) and chitosan (CS); Inner layer: co-axial nanofibers with core made of polycaprolactone and collagen, and shell of doxycycline and polyethylene oxide | CS (polymer), collagen (protein) and doxycycline (antibiotic); each layer contained one main inducer of biological activity | - Porous, flexible, mechanically resilient and wettable aligned fiber meshes were produced; - Absence of cytotoxic effects against keratinocyte cells even with quick release of drug; - Guaranteed prolonged protection of the payload (12 months); - Expression of matrix metalloproteinase-2 enzyme was inhibited, and ECM remodeling was promoted. | [78] |
Outer layer: polycaprolactone (PCL) Middle layer: PCL and type I collagen Inner layer: type I collagen and Melilotus officinalis extract | Collagen (protein) and Melilotus officinalis extract (plant extract) | - Smooth and defect-free three-layer nanofiber structures were obtained; - In vitro cell studies verified the fibroblast cells viability; - 18-day in vivo studies demonstrated the scaffold to induce proper re-epithelialization in diabetic wounds and to instigate collagen production and deposition in the newly formed skin. | [54] | ||
Outer layer: PCL Middle layer: polyvinyl pyrrolidone (PVP) and ciprofloxacin Inner layer: poly(acrylic acid) (PAA) | Ciprofloxacin (antibiotic) | - The scaffolding system displayed great mechanical resilience, with the PCL outer layer exhibiting lower wettability, adherence, and moisture uptake than the remainder layers; - Drug release was guaranteed in a sustained manner and was influenced by loading amount on the scaffold. | [90] | ||
Outer layer: poly(vinyl alcohol (PVA) and nanobioglass (nBG) Middle layer: CS and PVA Inner layer: CS | nBG (inorganic particles) and CS (polymer) | - The multilayer mesh exhibited excellent biocompatibility, antibacterial activity and regenerative effects; - Each layer allowed for a microenvironment to be generated so optimal performances of each component could be attained; - In vivo wound model revealed the mesh to significantly accelerate and enhance healing, in terms of complete re-epithelialization, improved collagen alignment and formation of skin appendages. | [41] | ||
Double Layer Mesh | Inner layer: gelatin (GN) with keratin Outer layer: polyurethane (PU) | Keratin (protein) | - Nanofibers presented a uniform morphology and bead-free structure; - Fibroblast-like cells attachment was improved (increased cell spreading) and proliferation was accelerated; - Engineered meshes promoted faster vascularization, facilitating wound repair and growth of thicker epidermis. | [67] | |
Inner layer: CS, PVA and deferoxamine Outer Layer: SA and PVA | CS (polymer) and deferoxamine (immunomodulatory drug) | - The double layer dressing displayed high swelling degree, sufficient water-vapor permeation, and high drug entrapment efficiency with a sustained release up to 48 h; - Meshes antibacterial effectiveness was confirmed; - The dressing was also deemed cytocompatible, with in vitro scratch testing revealing wound healing potential. | [40] | ||
Core-Shell Nanofibers | Shell: polyethylene oxide (PEO) and PCL Core: hyaluronic acid (HA), keratin and metformin hydrochloride | HA (biopolymer), keratin (protein) and metformin hydrochloride (biguanide antihyperglycemic agent) | - Shell structure guaranteed a prolonged released of the core-entrapped bioactive agents; - In vitro cell cultures demonstrated the enhanced biocompatibility of the engineered core-shell fibers and attested to their efficacy as drug delivery platforms. | [68] | |
Shell: PEO, CS and vancomycin Core: PVP, GN and imipenem/cilastatin | CS (polymer) and vancomycin and imipenem/cilastatin (antibiotics) | - Core-sell nanofibers displayed a smooth morphology with no cytotoxic evidence against fibroblastic cells; - Shell structure protected antibiotic at the core, guaranteeing a prolonged liberation, while the antibiotic at the shell experienced a faster release; - Nanofibers exhibit significant antibacterial profile against bacteria prevalent in DFUs. | [23] | ||
Shell: PU Core: starch and HA | HA (biopolymer) | - Porous core-shell structures were obtained; - In vitro cell morphology, viability and attachment were enhanced in the presence of the HA-loaded scaffold; - In vivo studies demonstrated the scaffolds to accelerate wound healing. | [81] | ||
Shell: poly-D-L-lactide-glycolide (PLGA) Core: insulin | Insulin (peptide hormone) | - Core-shell fibers sustained the release of insulin for 4 weeks, guaranteeing a balanced moist environment as well compared to single layer meshes; - Nanofibers reduced the amount of type I collagen in vitro but increased the transforming growth factor-beta (TGF-β) content in vivo and promoted diabetic wound repair. | [91] | ||
Shell: PLGA, vancomycin and gentamycin Core: recombinant human platelet-derived growth factor-BB (rhPDGF-BB) | Vancomycin and gentamycin (antibiotics) and rhPDGF-BB (growth factor) | - Scaffolds guaranteed a sustained release of growth factor and antibiotics for 3 weeks; - They also decreased phosphatase and tensin homolog content, enhanced angiogenesis marker presence (CD31), and accelerated healing in early-stage infected diabetic wounds. | [22] | ||
Single Layer Mesh | PLGA modified with recombinant human epidermal growth factor (rhEGF) and Aloe vera extract | rhEGF (growth factor) and Aloe vera (plant extract) | - Uniform, bead free meshes of improved porosity were obtained; - Presence of rhEGF and the extracts improved fibroblast proliferation and accelerated significantly wound closure and reepithelization in an in vivo full thickness wound mice model. | [46] | |
GN modified with human placenta-derived mesenchymal stem cells (hPDMSCs) and platelet-rich plasma (PRP) | hPDMSCs (stem cells) and PRP (blood components) | - Clinical testing was conducted on 28 patients with DFUs, from which 18 were treated with the smooth, homogenous nanofibers mats with and without PRP; - Cell proliferation and wound closure were significantly enhanced by hPDMSCs, however, PRP had little impact on the outcomes; - Pain was significantly reduced in the presence of the engineered nanofibers as compared to conventional standard care therapies (control group). | [49] | ||
PCL and GN composite containing silicate-based bioceramic particles of nagelschmidtite (NAGEL) | NAGEL (inorganic particles) | - The scaffolding system promoted the adhesion, proliferation and migration of human umbilical vein endothelial cells (HUVECs) and human keratinocytes (HaCaTs) in vitro; - In vivo evaluations demonstrated their ability in inducing angiogenesis, collagen deposition and re-epithelialization, as well as in inhibiting inflammation. | [92] | ||
Hydroxypropyl methylcellulose (HPMC) and PEO loaded with β-glucan | β-glucan (immunomodulatory drug) | - Electrospinning Nanospider™ technology ensure the reproducible and reliable production of nanofibers; - The scaffolds exhibited no cellular toxicity in vitro; - Wound healing assessment in a wound model confirmed the significant improvement introduced by βG-nanofibers. | [93] | ||
Poly(L-lactic acid) (PLLA) and dimethyloxalylglycine-loaded mesoporous silica nanoparticles (MSi NPs) | Dimethyloxalylglycine (immunomodulatory drug) and MSi NPs (inorganic particles) | - The engineered aligned porous meshes stimulated the proliferation, migration and angiogenesis-related gene expression of endothelial cells; - In vivo study demonstrated the meshes’ ability to improve neo-vascularization, re-epithelialization and collagen formation, while inhibiting inflammatory reactions in the diabetic wound bed. | [94] | ||
GN, arabinoxylan ferulate (AXF) and silver sulfadiazine | AXF (polysaccharide) and silver sulfadiazine (inorganic compound) | - Continuous, homogeneous fibers were attained with excellent biocompatibility and antimicrobial profiles; - Prolonged liberation of silver compound was guaranteed potentiating the scaffold testing in in vivo scenarios. | [95] | ||
ECM-componential collagen, PCL and bioactive glass nanoparticles (BGNs) | Collagen (protein) and BGNs (inorganic particles) | - Endothelial cell attachment and proliferation were enhanced; - Angiogenesis marker CD31 expression was upregulated in vitro; - Angiogenesis was also improved in vivo, by greatly upregulating the mRNA and protein expressions of hypoxia-inducible factor 1-α (Hif-1α), vascular endothelial growth factor (VEGF), collagen I and α-smooth muscle actin (α-SMA); - Granulation tissue formation, collagen matrix remodeling and epidermis differentiation were accelerated. | [56] | ||
Bixin-loaded PCL nanofibers | Bixin (carotenoid pigment extracted from Bixa orellana L. seeds) | - Increasing bixin concentration resulted in higher polymeric solution electrical conductivity and, consequently, in smaller fiber diameters; - Bixin release kinetics was guaranteed for 14 days (30–40% release in the first 10 h); - The bixin-loaded meshes accelerated wound healing while reducing the scar tissue area. | [52] | ||
PCL and Gymnema sylvestre | Gymnema sylvestre (plant extract) | - Scaffolds exhibited good wettability and enhanced mechanical properties; - Contact-mediated bacterial inhibition was achieved against Gram-positive and Gram-negative bacteria; - Scaffolds were identified as cytocompatible towards fibroblasts. | [30] | ||
PU and carboxymethyl cellulose (CMC) nanofibers containing Malva sylvestris extract | Malva sylvestris (plant extract) | - Meshes allowed great fluid absorption and sustained release of the extract; - Significant antibacterial activity was observed; - In vivo wound-healing testing indicated the scaffold accelerated healing significantly, aside from lowering acute and chronic inflammations; - Collagen deposition and neovascularization were also instigated. | [31] | ||
Poly(lactic acid) (PLA) and hyperbranched polyglycerol (HPG) modified with curcumin | Curcumin (plant extract) | - Meshes were deemed highly hydrophilic, absorbent and with great drug uptake; - In vitro cell viability, adhesion and proliferation were instigated as well as cell migration (scratch test). | [53] | ||
Neurotensin-loaded PLGA and cellulose nanocrystals (CNCs) composite | Neurotensin (neuropeptide) | - PLGA/CNCs nanofibers showed excellent cytocompatibility and facilitated fibroblast adhesion, spreading and proliferation; - Neurotensin could be released from the mats in a sustained manner for up 2 weeks; - In vivo data reported the composite abilities to induce faster epidermal and dermal regeneration, while decreasing the expressions of the inflammatory cytokines interleukin-1β (IL-1β) and IL-6. | [70] | ||
GN and bacterial cellulose (BC) modified with metformin and glybenclamide | Metformin and glybenclamide (diabetic drugs) | - Nanofibers were produced using a portable electrohydrodynamic gun with great homogeneity; - Diabetic wounds treated with nanofibers loaded with glybenclamide revealed moderate to complete re-epithelialization and well-formed granulation tissue, a result superior to the metformin-modified fibers; - TNF-α levels were significantly reduced with both drugs, but again glybenclamide was more effective. | [96] | ||
PLA and doxycycline | Doxycycline (antibiotic) | - Antibiotic homogeneous distribution along the fibers for a sustained release was achieved; - The mats’ mechanical features, water-vapor permeability and absorbency met the requirement for wound dressings; - In vitro data confirmed the mats’ cytocompatibility and antibacterial profile; - In vivo full-thickness wound healing was also stimulated. | [21] | ||
PVA incorporating active silk sericin | Silk sericin (protein) | - Dressings were endowed with free radical scavenging capacity, antibacterial activity, swelling capacity, and biocompatibility due to the incorporation of silk sericin; - Fibroblasts and keratinocytes spreading and proliferation were improved; - The nanofibers exhibited excellent antioxidant potential without hampering cell viability even under H2O2 driven oxidative stress; - In vivo tolerance to the engineered dressing was confirmed over 4 weeks of testing, with no inflammatory events being triggered. | [64] | ||
CS, PVA and zinc oxide nanoparticles (ZnO NPs) | ZnO NPs (inorganic particles) | - CS/PVA/ZnO nanofibrous meshes possessed exceptional antibacterial activity against DFUs-prevalent bacteria; - They also exhibited excellent antioxidant potential; - In vivo wound healing studies showed that CS/PVA/ZnO meshes accelerated wound healing. | [34] | ||
PCL, ZnO NPs and Urtica dioica | ZnO NPs (inorganic particles) and Urtica dioica (plant extract) | - Incorporation of Urtica dioica and ZnO NPs improved the fibers’ water uptake and controlled the release of the plant extract; - Antibacterial activity was augmented and cell cytotoxicity was diminished in the presence of the hybrid scaffold; - Cell adhesion and, consequent, scaffold integration was instigated. | [35] | ||
PVA, astragalus and astragaloside IV liposomes. | Astragalus (polysaccharide, plant extract) and astragaloside IV (cycloartane-type triterpene obtained from Astragalus membranaceus) | - In vivo testing revealed the nanofibers to inhibit inflammation, enhance deposition of collagen and the repair of regenerated epithelium, and effectively strengthen wound healing of diabetic rats. | [97] | ||
PVA, SA and silk fibroin (SF) fibers loaded with asiaticoside. | SF (protein) and asiaticoside (pentacyclic triterpenoid isolated from Centella asiatica plant) | - Homogeneous nanofibers with sustained asiaticoside liberation over extended periods were electrospun; - Mats exhibited low cytotoxicity, promoting improved cell migration and anti-microbial efficacy; - In vivo testing revealed wound healing efficacy and abilities to restore normal skin structure. | [79] | ||
PVA, SF, type I collagen and S-Nitrosoglutathione | SF (protein), type I collagen (protein) and S-Nitrosoglutathione (nitric oxide donor) | - Continuous, bead free and randomly oriented nanofibers meshes were obtained with a highly porous morphology; - In vitro evaluations attested to the scaffold biocompatibility with a high level of cell attachment, expansion, inter-cellular connections and proliferation, mainly promoted by type I collagen; - Nitric oxide release, essential for effective wound healing, was guaranteed for 1 day. | [58] | ||
Poly-(L-lactide-co-caprolactone) (PLCL) and SF loaded with Huangbai Liniment | SF (protein) and Huangbai Liniment (plant extract) | - Smooth and bead-free nanofibers allowed for a sustained release of the natural-origin drug; - Antibacterial effects were observed against Gram-positive and Gram-negative bacteria; - In vitro cell adhesion and proliferation were enhanced; - In vivo testing demonstrated the loaded nanofibers to instigate the expression of the TGF-β signaling pathway and collagen and to inhibit pro-inflammatory factors, thus effectively promoting healing. | [61] | ||
Electrospinning and Entrapment-Graft | Single Layer Mesh | PLGA-hydroxypropyltrimethyl ammonium chloride chitosan (HACC) composite | HACC (polymer) | - Effective antibacterial activity towards both Gram-positive and Gram-negative bacteria; - Meshes were cytocompatible, significantly stimulating adhesion, spreading and proliferation of fibroblasts and keratinocytes; - PLGA-HACC exhibited excellent wound healing efficacy in vivo. | [42] |
Electrospinning combined with a Spray Phase-Inversion Method | Double-Layer Meshes | PU combined with fibrin fibers loaded with platelet lysate | Fibrin (protein) and platelet lysate (blood component) | - The bilayer dressing allowed a sustained release of bioactive platelet-derived growth factors; - The engineered scaffold also significantly accelerated wound closure in in vivo full-thickness wounds; - Histological data demonstrated the scaffold’s effectiveness in increasing re-epithelialization and collagen deposition. | [98] |
Electrospinning followed by Hydrogel Loading | Fiber-Hydrogel Composite | PLA nanofibers loaded with HA, valsartan, and ascorbic acid hydrogel | HA (biopolymer), valsartan (immunomodulatory drug) and ascorbic acid (vitamin C) | - Scaffolds offered a large surface area for enhanced drug solubility, oxygen permeability, and fluid uptake; - Presence of valsartan significantly impacted the re-epithelization rate, accelerating it; - Scaffolds also reduced the number of inflammatory cell infiltrates at the wound site. | [99] |
Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanofibers modified with GN-methacryloyl (GNMA) hydrogels containing epidermal growth factors (EGFs) | EGFs (growth factors) | - Patches promoted cells migration and proliferation and enhanced angiogenesis in vitro; - In vivo wound healing testing in diabetic rats showed the patches stimulated favorable cell responses, angiogenesis and rapid wound healing. | [47] | ||
SA, SF and amniotic fluid | SF (protein) and amniotic fluid (complex substance containing a wide range of growth factors) | - SF fibers were successfully linked to the SA-based hydrogel formulation; - Sustained release of amniotic fluid was guaranteed at the optimal ratio with SA (superior amount of amnionic fluid); - Fibroblast-like cells proliferation, spreading, and secretion of collagen were enhanced with increasing concentrations of amniotic fluid. | [100] | ||
Electrospinning followed by Cryogenic Cutting and Thermal Treatment | Cylindrical 3D Scaffolds made of Radially or Vertically Aligned Nanofibers | PCL, GN and Pluronic-F-127, modified with bone marrow mesenchymal stem cells (BMSCs) | BMSCs (stem cells) | - Scaffolds can be customized with different sizes, depths, and shapes for a variety of type 2 diabetic wounds; - They were also shape-recoverable in the atmosphere and water following compression; - Enhanced the formation of granulation tissue, promoting angiogenesis, and facilitating collagen deposition; - Inhibited the expression of pro-inflammatory cytokines IL-6 and tumor necrosis factor-α (TNF-α) and promote the expression of anti-inflammatory cytokines IL-4 and IL-10. | [74] |
Electrospraying | Fibrous Sponge Functionalized with Co-axial Microparticles | Insulin-encapsulated SF microparticles loaded onto SF sponge | SF (protein) | - SF microparticles guaranteed the sustained release of insulin for up to 28 days; - Insulin retained its bioactivity and promoted cell migration; - The engineered dressing was seen to accelerate wound closure, collagen deposition and vascularization. | [62] |
Weft Knitting | Three-Layer Fabric | Polyethylene terephthalate (PET) and PU yarns modified with quaternary ammonium salt (QAS) | QAS (cationic salt; organic particles) | - Effective exudates management, with optimal moisture balance, and oxygenation of the wound (porous nature); - Excellent broad-spectrum antimicrobial activity, with non-leaching of salts, thus preventing the development of mutations or microbial resistance; - Durable and cost-effective dressing. | [89] |
Knitting followed by Grafting (adjustable curing and impregnation conditions) | Cellulosic Textile Woven | Cellulosic textile woven grafted with alginate and Carthamus tinctorius polymer extract | Alginate (polymer) and Carthamus tinctorius polymer extract (plant extract) | - Grafting was successfully conducted without compromising textile properties; - Excellent biocompatibility, with increased cell viability after grafting; - Antimicrobial testing against four of the most prevalent DFU bacteria demonstrated the engineered dressing potent antimicrobial effect. | [29] |
Tappi T 205 sp-02 (standard compression method of pulp and paper industry) | Fibrous paper | Cellulose fibers from bleached softwood Kraft lignin modified with silver phosphate | Silver phosphate (inorganic salt) | - Efficient antimicrobial activity against Staphylococcus aureus bacterium; - Antimicrobial effectiveness equal or superior to commercial products. | [101] |
Aqueous Phase Fiber Reassembly | 3D Fibrous Scaffold | PCL and collagen nanofibers loaded with doxycycline hyclate-modified halloysite nanotubes and cephalexin | Collagen (protein), doxycycline hyclate (tetracycline antibiotic), halloysite nanotubes (inorganic nanostructures made of alumina-silicate) and cephalexin (antibiotic) | - The scaffold exhibited high water absorption capacity and swelling capacity, potentially reducing dressing change frequency in DFUs; - It also displayed excellent antibacterial activity against Escherichia coli and Staphylococcus aureus bacteria; - Additionally, the dressing demonstrated good biocompatibility, significantly improving wound healing. | [57] |
Electrohydrodynamic Cryoprinting | Micropatterned fiber scaffolds | PC loaded with adipose-derived MSCs (AMSCs) | AMSCs (stem cells) | - Efficient pore formation along the scaffold for increased surface roughness (facilitated cell adhesion); - In vitro enhanced secreting of growth factors and chemokines, which promoted fibroblast migration and vascular endothelial cell tube formation; - Augmented scarless collagen deposition and angiogenesis, and reduction of pro-inflammatory reactions in in vivo experimentation. | [75] |
Pressurized Gyration | Single Layer Mesh | PVP and PCL loaded with pioglitazone hydrochloride (PHR) | PHR (immunomodulatory drug) | - PHR-loaded fibrous mats expedited diabetic wound healing in type-1 diabetic rats without triggering any cytotoxic effect on cells; - Additionally, mats improved neutrophil infiltration, edema, and reduced inflammation, aside from increasing epidermal regeneration and fibroblast proliferation. | [102] |
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Felgueiras, H.P. Emerging Antimicrobial and Immunomodulatory Fiber-Based Scaffolding Systems for Treating Diabetic Foot Ulcers. Pharmaceutics 2023, 15, 258. https://doi.org/10.3390/pharmaceutics15010258
Felgueiras HP. Emerging Antimicrobial and Immunomodulatory Fiber-Based Scaffolding Systems for Treating Diabetic Foot Ulcers. Pharmaceutics. 2023; 15(1):258. https://doi.org/10.3390/pharmaceutics15010258
Chicago/Turabian StyleFelgueiras, Helena P. 2023. "Emerging Antimicrobial and Immunomodulatory Fiber-Based Scaffolding Systems for Treating Diabetic Foot Ulcers" Pharmaceutics 15, no. 1: 258. https://doi.org/10.3390/pharmaceutics15010258
APA StyleFelgueiras, H. P. (2023). Emerging Antimicrobial and Immunomodulatory Fiber-Based Scaffolding Systems for Treating Diabetic Foot Ulcers. Pharmaceutics, 15(1), 258. https://doi.org/10.3390/pharmaceutics15010258