Innovative Strategies in 3D Bioprinting for Spinal Cord Injury Repair
Abstract
:1. Introduction
2. 3D Bioprinting Technologies for SCI Repair
2.1. Overview of 3D Bioprinting Techniques and Bioinks
2.2. Role of Stem Cells in 3D Bioprinting for SCI Repair
3. Innovative Scaffold Designs for Enhanced Regeneration
3.1. Enhancing Neural Repair with Conductive Scaffolds
3.2. Biofunctionalization of Scaffolds with Neurotrophic Factors, Drugs, and Exosomes
3.3. Multi-Channel Conduits and Axial Structured Scaffolds: Promoting Neuronal Connectivity
4. Challenges and Future Perspectives
4.1. Technical and Biological Challenges in 3D Bioprinting for SCI
4.2. Future Trends in 3D Bioprinting-Based Therapies
5. Summary
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Characteristic | Extrusion-Based | Inkjet-Based | Laser-Assisted | Stereolithography |
---|---|---|---|---|
Applicable Bioinks | Broad spectrum: hydrogels, thermoplastics, and composites | Best for low-viscosity, aqueous solutions | Limited to photopolymerizable materials | Restricted to UV-sensitive resins and specific photopolymers |
Precision | Medium: Ideal for building foundational structures | High: Great for detailed surface features, less so for complex 3D forms | Very High: Excellent for intricate micro-architectures | Extremely High: Capable of nano-scale precision |
Printability | Robust for large, continuous structures. | Efficient in producing high-resolution patterns, suitable for microfluidics | Excellent for creating fine and complex vascular networks | Best for achieving complex geometries with high accuracy |
Primary Applications | - Scaffold construction - Soft tissue engineering - Bone and cartilage regeneration | - Skin substitutes - Tissue chips for drug testing - Simple organoids | - Microvasculature fabrication - Nerve regeneration constructs - Precision cartilage implants | - Dental applications - Complex tissue models - High-precision implants |
Advantages | - Versatile with material types - Supports multi-material printing - Continuous material deposition ideal for large constructs | - High printing speed - Low material waste - Capable of printing gradients - Precise droplet control | - Ultra-high resolution - Minimal cell damage due to non-contact process - Ideal for high-detail tissue layers | - Unmatched precision - Capable of printing complex internal structures - Smooth surface finish, critical for tissue interfaces |
Disadvantages | - Lower resolution compared to laser methods - Potential for high shear stress on cells - Slower build times | - Limited to less viscous materials - Lower structural integrity in larger prints - Potential for cell damage during droplet ejection | - Applied in nerve regeneration and wound healing - Supports angiogenesis and axonal regrowth | - High cost and complexity - Limited bioink selection - UV exposure can adversely affect cell viability |
Recent Innovations | - Incorporation of real-time mechanical feedback for better structural accuracy - Development of shear-thinning bioinks to reduce cell damage | - Advancement in droplet-based systems to improve cell viability - Introduction of on-demand printing with fewer material constraints | - Use of multi-photon polymerization for even finer details - Integration of biocompatible photo-initiators to expand material choices | - Development of hybrid resins that allow for faster curing without compromising biocompatibility - Improvement in software algorithms for optimizing print paths |
References | [24,25] | [26,27] | [23,28] | [23,29] |
Material Category | Key Features | Applications | Challenges | References |
---|---|---|---|---|
Natural Polymers | Collagen: Abundant, supports cell adhesion, low immunogenicity, facilitates tissue integration. | - Enhances axonal guidance and reduces scar formation. - Ideal for scaffolds in neural tissue repair. | - Requires crosslinking for stability. - Rapid enzymatic degradation. | [33,34] |
Gelatin and GelMA: Easy modification, supports 3D bioprinting, promotes cell proliferation. | - Used in 3D bioprinting of scaffolds. - Facilitates neural differentiation. | - Mechanical weakness; needs combination with stronger polymers. - Fast degradation. | [35,36] | |
Hyaluronic Acid: Natural hydrating agent, promotes cell migration and proliferation. | - Encourages axonal growth and neural tissue repair. - Useful in hydrogels for spinal injury treatment. | - Weak structural integrity. - Rapid breakdown under physiological conditions. | [36,37,38] | |
Polysaccharide-based | Alginate: Forms stable hydrogels, highly biocompatible, easily modified for drug delivery. | - Applied in controlled release systems for drug delivery. - Supports 3D cell culture. | - Limited mechanical properties. - Requires modification for cell adhesion. | [36,39,40] |
Protein-based | Fibrin: Excellent compatibility, promotes vascularization, fast degradation. | - Useful in early-stage wound healing and tissue repair. - Supports cell adhesion and proliferation. | - Rapid breakdown, potentially leading to instability. - Careful handling required to avoid rapid clotting. | [36,41,42] |
Polysaccharide-based | Chitosan: Biodegradable, antimicrobial, and supports hemostasis. | - Applied in nerve regeneration and wound healing. - Supports angiogenesis and axonal regrowth. | - Variable mechanical properties. - High immunogenicity in some formulations. | [36,43] |
Synthetic Polymers | Polycaprolactone: Strong, long-lasting, shape-memory capabilities. | - Ideal for long-term implants and load-bearing applications. - Supports tissue engineering scaffolds. | - Slow degradation rate, potential persistence in the body. - Requires surface modification for cell adhesion. | [36,44] |
Polyethylene Glycol: Versatile, non-toxic, customizable degradation. | - Used in drug delivery systems. - Reduces inflammation and oxidative stress. | - Lacks intrinsic biological activity. - Often needs to be combined with bioactive materials. | [36,45] | |
Poly(lactic-co-glycolic acid): FDA-approved, controlled degradation, supports drug release. | - Popular for drug delivery vehicles. - Enhances tissue regeneration. | - Acidic degradation by-products may cause inflammation. - Requires precise control of degradation rate. | [46] | |
Elastomers | Poly(glycerol sebacate): Elastic, suitable for dynamic environments, promotes vascularization. | - Applied in soft tissue engineering, such as cardiac and neural tissues. - Biodegradable. | - Limited cell adhesion due to hydrophobicity. - Requires surface modification. | [47] |
Biocomposites | Decellularized Extracellular Matrix: Mimics native tissue, supports cell attachment. | - Enhances tissue integration in vivo. - Promotes cell-specific differentiation. | - Complex production process. - Potential variability in composition and residual immunogenicity. | [48] |
Nanomaterials | Carbon-based (CNTs): Conductive, promotes cell growth, excellent mechanical properties. | - Useful in developing conductive scaffolds for neural applications. - Enhances electrical signal conduction. | - Potential cytotoxicity. - Difficult to functionalize and process. | [49,50] |
Thermoresponsive Polymers | Methylcellulose: Injectable, biocompatible, forms gels at body temperature. | - Ideal for minimally invasive cell delivery systems. - Supports stem cell transplantation. | - Poor mechanical strength. - Needs reinforcement with other materials for structural applications. | [39,51] |
Biodegradable Plastics | Polyhydroxyalkanoates: Biodegradable, microbial origin, tunable properties. | - Sustainable material for tissue engineering. - Useful in slow-release drug delivery. | - High production cost. - Variability in mechanical properties based on the microbial source. | [52] |
Advanced Proteins | Silk Fibroin: High tensile strength, biocompatible, slow-degrading, versatile processing. | - Applied in long-term implants and tissue scaffolding. - Supports cell attachment and growth. | - Complex processing and purification required. - Potential immunogenicity if not properly processed. | [33,53] |
Self-assembling Materials | Self-assembling Peptides: Customizable, forms nanofibers mimicking the extracellular matrix. | - Useful in targeted drug delivery and regenerative medicine. - Supports neural tissue formation. | - High cost and synthesis complexity. - Potential immunogenicity depending on peptide sequence. | [36] |
Bioink | Cell Type | Printing Method | In Vitro/In Vivo | Innovative Technologies | Outcomes | References |
---|---|---|---|---|---|---|
Enhancing conductivity | ||||||
Polycaprolactone and PPy | Olfactory EMSC | Extrusion | In vitro | Enhancing conductivity by PPy | - PPy improved the conductivity of 3D-printed scaffolds. - The conductive scaffolds promoted the differentiation of MSCs into Schwann cell-like phenotypes, enhancing the secretion of nerve growth factors and neurite outgrowth. | [70] |
GelMA, HAMA, and PEDOT: sulfonated lignin | NSC | Extrusion | In vivo | Enhancing conductivity by PEDOT | - PEDOT improved the conductivity of scaffolds by nearly tenfold and reduced impedance. - The 3D bioprinted scaffolds supported high survival rates and increased differentiation of encapsulated NSCs in vitro and in vivo. | [73] |
GelMA, PEGDA, PEDOT: chondroitin sulfate methacrylate, and TA | NSC | Extrusion | In vitro | Enhancing conductivity by PEDOT | - Doping PEDOT with chondroitin sulfate improved its water-solubility, electrical properties, and biocompatibility. - The axially stacked 3D bioprinted scaffold tguided neurite outgrowth. | [74] |
GelMA, PEGDA, PEDOT: chondroitin sulfate methacrylate, and TA | NSC | Extrusion | In vivo | Enhancing conductivity by PEDOT | - The conductive 3D bioprinted scaffold showed high conductivity, shape fidelity, shear-thinning, and self-healing properties. - The 3D bioprinted scaffold enhanced neuronal differentiation and locomotor function recovery in SCI rats. | [75] |
PEGDA and CNTs | NSC | Stereolithography | In vitro | Enhancing conductivity by CNTs | - Stereolithography enabled intricate microarchitectures and controlled porosity. - Improving electrical properties by CNTs enhanced the proliferation and differentiation of NSCs seeded on the 3D-printed scaffolds. | [49] |
Pentenoate-functionalized HA & gelatin and GNR | NSC | Extrusion | In vitro | Enhancing conductivity by GNR | - GNRs enhance conductivity and stiffness. - GNRs are not sufficient alone to drive NSC’s differentiation without the electrical stimulation. | [76] |
Biofunctionalization (Neurotrophic Factors, Drugs, and Exosomes) | ||||||
Collagen and chitosan | NSC | Extrusion | In vitro (In vivo—without NSC laden) | Adding BDNF | - Integrating BDNF during the 3D printing process prolonged release of BDNF. - The 3D bioprinted scaffold improved locomotor function, nerve fiber regeneration, synaptic connections, and remyelination in SCI rats. | [86] |
PEGDA with NGF-loaded PLGA nanoparticles | PC12 cell | Stereolithography | In vitro | Adding NGF-loaded PLGA nanoparticles | - Incorporating PLGA nanoparticles encapsulating BSA and NGF enabled sustained release of bioactive factors. - The nanoparticle loaded scaffold significantly increased neurite length and effectively guided neurite extension. | [87] |
GelMA and acrylate β-cyclodextrin | NSC | Extrusion | In vivo | Adding OGT inhibitor | - OGT inhibitor-laden 3D bioprinted scaffolds allow for localized, controlled release of bioactive molecules. - The scaffolds promoted neuronal differentiation by inhibiting the Notch signaling pathway in SCI rats. | [91] |
GelMA | PC12 cell | Extrusion | In vitro (In vivo—without PC12 cell laden) | Adding PTEN-interfering siRNAs-loaded exosomes | - The 3D-printed scaffold encapsulated PTEN-interfering siRNAs-loaded exosomes. - siRNAs inhibited PTEN, which in turn enhanced mTOR phosphorylation and facilitated axonal regeneration. | [95] |
GelMA | NSC | Extrusion | In vitro (In vivo—without NSC laden) | Adding plant-derived exosomes loaded with isoliquiritin | - The 3D-printed scaffold incorporated isoliquiritin encapsulated within plant-derived exosomes. - The scaffold controlled drug release and reduced inflammation by modulating microglial polarization and increasing phosphorylated AKT expression. | [97] |
Multi-Channel Conduits and Axially Structured Scaffolds | ||||||
Matrigel, gelatin/fibrin, and GelMA | NPC and OPC | Extrusion | In vitro | Multi-Channel Conduits | - The 3D multichannel scaffold with 150 μm diameter channels incorporated sNPCs and OPCs. - The sNPCs differentiated into neurons and OPCs matured into oligodendrocytes, creating a neural relay system. | [39] |
Alginate and collagen | Schwann cell and endothelial cell | Extrusion | In vivo | Multi-Channel Conduits | - 3D multichannel scaffold, designed to align Schwann cells and endothelial cells for axon regrowth and migration. - Increasing the number of channels led to improved outcomes. | [40] |
PEGDA and GelMA | NPC | Microscale continuous projection | In vivo | Multi-Channel Conduits | - The 3D biomimetic scaffold with 200 μm diameter channels was created through continuous projection printing, allowing fast and high-resolution customized rodent spinal cords. - The scaffold enhanced mechanical properties and cellular attachment, leading to functional recovery. | [107] |
GelMA and HAMA | NSC | Extrusion | In vivo | Axially Structured Scaffolds | - The axially structured 3D bioprinted scaffold was designed to resemble densely arranged bundles of nerve fibers. - The scaffold enhanced neural relay formation and overall neural regeneration in SCI rats. | [111] |
Inner layer: HA derivatives and N-cadherin modified sodium alginate Outer layer: gelatin/cellulose nanofiber | NSC | Extrusion | In vitro (In vivo—without NSC laden) | Axially Structured Scaffolds | - Hierarchically structured scaffolds with dual-network hydrogels, where the inner layer supports NSC migration and neuronal differentiation, and the outer layer protects NSCs by releasing reactive species scavengers. - The scaffold improved neural network formation, inhibited glial scar formation, and reduced collagen deposition in SCI rats. | [112] |
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Kim, D.Y.; Liu, Y.; Kim, G.; An, S.B.; Han, I. Innovative Strategies in 3D Bioprinting for Spinal Cord Injury Repair. Int. J. Mol. Sci. 2024, 25, 9592. https://doi.org/10.3390/ijms25179592
Kim DY, Liu Y, Kim G, An SB, Han I. Innovative Strategies in 3D Bioprinting for Spinal Cord Injury Repair. International Journal of Molecular Sciences. 2024; 25(17):9592. https://doi.org/10.3390/ijms25179592
Chicago/Turabian StyleKim, Daniel Youngsuk, Yanting Liu, Gyubin Kim, Seong Bae An, and Inbo Han. 2024. "Innovative Strategies in 3D Bioprinting for Spinal Cord Injury Repair" International Journal of Molecular Sciences 25, no. 17: 9592. https://doi.org/10.3390/ijms25179592