Enhancing Wound Healing Through Secretome-Loaded 3D-Printed Biomaterials
Abstract
1. Introduction
2. Skin Structure and Physiology
3. Wound Healing Process
4. Treatments of Wound
4.1. Standard Treatments of Wound
4.2. Alternative Treatments of Wound
5. Biomaterials
5.1. Naturals Biomaterials
5.2. Synthetic Biomaterials
6. Secretome
6.1. Extracellular Vesicles (EVs)
6.2. Fundamental Mechanism of Secretome
6.3. Uses of Secretome
7. Secretome-Loaded Biomaterials
8. 3D Bioprinting Technology
8.1. Integration of Secretome with 3D-Printed Biomaterials
8.2. Preclinical and Clinal Applications of Secretome-Loaded 3D-Printed Biomaterials
8.3. Ideal 3D-Bioprinting Materials Requirements
8.4. 3D-Bioprinting Techniques
9. Challenges and Future Perspectives
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
EVs | Extracellular vesicles |
ECM | Extracellular matrix |
3D | Three-dimensional |
PDGF | Platelets derived growth factor |
TGF-α | Transforming growth alpha |
TGF-β | Transforming growth beta |
FGF | Fibroblast growth factor |
IGF-1 | Insulin-like growth factor-1 |
ROS | Reactive oxygen species |
MMPs | Matrix metalloproteinases |
FTSG | Full-thickness skin graft |
STSG | Split-thickness skin graft |
MSCs | Mesenchymal stem cells |
PVA | Polyvinyl alcohol |
GAG | Glycosaminoglycan |
PLA | Polylactic acid |
PLGA | Poly(lactic-co-glycolic acid) |
PEG | Poly(ethylene glycol) |
CM | Conditioned medium |
Th | T helper cells |
IL | Interleukin |
VEGF | Vascular endothelial growth factor |
EGF | Epidermal growth factor |
MVEs | Multivesicular endosomes |
ILVs | Intraluminal vesicles |
MVBs | Multivesicular bodies |
RNA | Ribonucleic acid |
CT | Computed tomography |
MRI | Magnetic resonance imaging |
CAD | Computer-aided design |
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Function | Structure | Description | References |
---|---|---|---|
Protection | Epidermis | Serves as a physical barrier, protecting against environmental threats such as pathogens, chemicals, and physical injuries | [3,23] |
Sensation | Dermis | Enables the perception of touch, pressure, temperature, and pain, facilitating interaction with the environment | [24,25] |
Thermoregulation | Dermis and hypodermis | Contributes to body temperature regulation through mechanisms such as sweating and modulation of blood flow | [24,25,26,27,28] |
Excretion | Dermis | Aids in the excretion of metabolic waste products through sweat glands | [26] |
Immune function | Epidermis and dermis | Serves as an immunological barrier detecting and responding to pathogens | [3,29] |
Fluid balance | Epidermis | Prevents excessive water loss, thus maintaining proper hydration and fluid balance within the body | [24] |
Phases | Key Events | References |
---|---|---|
Hemostasis phase | Platelets are activated, and the collagen fibers then draw the platelets to form blood clots which are made up of fibronectin, fibrin, vitronectin, and thrombospondin | [4,8] |
Inflammation phase |
| [4,31] |
Proliferative phase |
| [4,32] |
Remodeling phase |
| [33] |
Treatments | Types | Description | Examples | References |
---|---|---|---|---|
Full-thickness Skin Graft (FTSG) | Autograft | Involves transplanting both the epidermis and entire dermis layers of the skin | Abdomen | [36] |
Split-thickness Skin Graft (STSG) | Autograft | Skin taken from the patient’s own body and can be used for large wounds, burns, and ulcers | Thigh skin grafts | [37] |
Allografts | Skin obtained from a human donor | Cryopreserved cadaveric skin | [38] | |
Xenografts | Skin derived from an animal source used as a temporary biological dressing | Porcine skin grafts | [38] | |
Wound Dressings | Hydrocolloid | Forms a gel upon contact with wound exudate, maintaining moisture. Best for wounds with minimal exudate | Duoderm | [39] |
Hydrogel | Provides moisture to dry wounds. Best for wounds with minimal exudate | Intrasite Gel, Aquaform | [40] | |
Transparent Film | Thin, adhesive, and waterproof dressing that allows wound visualization while preventing contamination | Tegaderm | [41] | |
Antimicrobial Dressing | Contains agents like iodine to reduce bacterial load and prevent infection | Iodoflex | [42] | |
Foam Dressing | Absorbs moderate to heavy exudate, maintains a moist environment, and provides cushioning | Mepilex | [37] |
Biomaterials | Types | Source | Key Properties | Limitations | Applications | References |
---|---|---|---|---|---|---|
Natural biomaterials | Collagen | Human and animal ECM (bovine, pig, mouse, marine) | Biocompatible and can be used in 3D-printed scaffolds for bone or tendon repair | Lack mechanical strength and requires modifications | Widely used in tissue engineering. | [51,52,53] |
Gelatin | Derived from partial hydrolysis of collagen | Biodegradable, biocompatible, and low immunogenicit | Poor viscosity and mechanical strength at high temperatures | Skin repair, tissue engineering, GelMA for cell encapsulation | [53,54,55] | |
Silk | Extracted from silkworm cocoons | Biocompatible, promotes wound healing phases, antibacterial with nanodiamond | Less effective against Gram-positive bacteria | Wound dressings and tissue engineering | [50,56,57] | |
Hyaluronic acid | Found in ECM of connective and epithelial tissues | Enhances cell adhesion, proliferation, differentiation, and water soluble | Immunoevasive in pathogens | Wound healing, 3D bioprinting, and viscosity enhancer | [54,58,59,60] | |
Alginate | Extracted from brown algae | Biocompatible, biodegradable, and supports cell growth | Poor cell adhesion | Wound healing and tissue regeneration | [61] | |
Chitosan | Crustacean shells | Antibacterial, modifiable, bioadhesive, and enhances drug delivery | Limited mechanical strength | Hydrogels, nanofibers, and drug delivery | [56,62,63] | |
Synthetic biomaterials | PLA | Plant-based from lactic acid monomers | Biodegradable thermoplastic and supports bone regeneration | Weak mechanical properties | Bone scaffolds and 3D printing with additives | [62,64,65] |
PVA | Synthetic polymer | Biocompatible, non-toxic and water soluble | Poor haemostasis, antibacterial activity, and hydrophilicity | Hemostatic dressings and wound healing with modifications | [66,67] | |
Polyglycolic acid (PGA) | Synthetic polymer | Fast degradation and high mechanical strength | Produced acidic degradation products | Tissue engineering | [68] | |
PEG | Synthetic polymer | Tunable, cell-encapsulating, and non-toxic | Requires modification to optimize its performance | Scaffolds and diabetic wound healing | [54,56,69] | |
Composite biomaterials | Polysaccharide-bioceramic composites | Natural polysaccharides with ceramic phases | Enhanced bioactivity, osteoconductivity, and mechanical reinforcement | Brittleness and complex fabrication | Bone tissue engineering and scaffold reinforcement | [70] |
Nanostructured polymer composites | Polymers with nanoparticles or nanofillers | Improved mechanical, thermal, and biological properties | Cost and scale-up challenges | Advanced wound healing, scaffold fabrication, and drug delivery | [71] |
Growth Factors | Role in Wound Repair | References |
---|---|---|
IL-1, IL-6, IL-8 | Promotes angiogenesis of wounds and regeneration of epithelium | [79,80] |
PDGF | Increased fibroblast and endothelial cell proliferation, migration, and invasion ability | [79] |
TGF | Promoted ECM remodeling, ultimately promotes wound healing and reduces scar formation | [80] |
bFGF | Migration and proliferation of fibroblasts | [81] |
VEGF | Proliferation and migration of endothelial cells, acceleration of wound angiogenesis, promotes migration of fibroblasts | [79] |
EGF | Promotes proliferation of fibroblasts | [79] |
Study | Biomaterials | Model | Findings | Limitations | References |
---|---|---|---|---|---|
Hyaluronic Acid Sponge with MSC Secretome | Hyaluronic acid sponge | In vivo (psoriasis skin model) | Porous sponge enables sustained release of MSC secretome, promoted 50% increase in keratinocyte proliferation, angiogenesis, and inflammation needed for dermal wound repair | Clinical efficacy not yet validated, limited to psoriasis model | [97] |
GelMA-PEGDA Hydrogels with MSC Secretome | GelMA and poly(ethylene glycol) diacrylate (PEGDA) hybrid hydrogels | In vitro (hyperglycemic human dermal fibroblasts) | Restored proliferation and migration of hyperglycemic fibroblasts to more than 85% wound closure, potential for diabetic wound healing | In vivo efficacy and long-term effects not assessed | [98] |
Alginate/ECM Hydrogel Patch with hMSC Secretome | Alginate combined with decellularized ECM | In vivo (rat skin wound model) | Accelerated wound closure rate of 92% by day 14, improved angiogenesis, and increased in collagen deposition | Limited to skin wound model | [94] |
Photopolymerizable GelMA Hydrogels with hADSC Secretome | GelMA hydrogels | In vitro (scratch assay, tube formation) | Enhanced fibroblast migration by 65% and angiogenesis, tunable release of secretome components | Requires in vivo validation, potential variability in hydrogel formulations | [99] |
Fibrin Glue with MSC secretome | Fibrin-based hydrogels | In vivo (rat intestinal anastomosis model) | Improved anastomotic healing, increased granulation tissue and collagen deposition, and promoted 1.8 fold angiogenesis | Focused on intestinal model, broader applications need exploration | [100] |
Bioprinting Techniques | Description | Advantages | Disadvantages | Examples of Biomaterials | References |
---|---|---|---|---|---|
Extrusion-Based Printing | Utilizes a fluid-dispensing mechanism and robotic system to extrude bioink as continuous cylindrical filaments |
| Increased mechanical stress reduces cell viability | GelMA-alginate and gelatin-fibrin | [108,117,118] |
Inkjet-Based Printing | Deposits bioink onto a substrate either as a continuous flow or discrete droplets using electronically controlled ink cartridges |
| Limited to low viscosity bioinks that can be ejected through a nozzle | Collagen, fibrinogen-alginate, hyaluronic acid | [53,119,120] |
Laser-Based Bioprinting | Uses laser-induced forward transfer to deposit bioink without physical contact, minimizing cellular stress |
| Expensive and complex control systems limit accessibility | Collagen-gelatin, alginat-MSC secretome | [53,118] |
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Rattanachot, T.; Lokanathan, Y.; Fauzi, M.B.; Maarof, M. Enhancing Wound Healing Through Secretome-Loaded 3D-Printed Biomaterials. Gels 2025, 11, 476. https://doi.org/10.3390/gels11070476
Rattanachot T, Lokanathan Y, Fauzi MB, Maarof M. Enhancing Wound Healing Through Secretome-Loaded 3D-Printed Biomaterials. Gels. 2025; 11(7):476. https://doi.org/10.3390/gels11070476
Chicago/Turabian StyleRattanachot, Tithteeya, Yogeswaran Lokanathan, Mh Busra Fauzi, and Manira Maarof. 2025. "Enhancing Wound Healing Through Secretome-Loaded 3D-Printed Biomaterials" Gels 11, no. 7: 476. https://doi.org/10.3390/gels11070476
APA StyleRattanachot, T., Lokanathan, Y., Fauzi, M. B., & Maarof, M. (2025). Enhancing Wound Healing Through Secretome-Loaded 3D-Printed Biomaterials. Gels, 11(7), 476. https://doi.org/10.3390/gels11070476