Strategy of Injectable Hydrogel and Its Application in Tissue Engineering

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Strategy of Injectable Hydrogel and Its Application in Tissue Engineering

Injectable hydrogels have emerged as a revolutionary biomaterial in tissue engineering (TE), offering minimally invasive delivery, structural adaptability to complex tissue geometries, and biomimetic properties akin to the extracellular matrix (ECM). Their ability to encapsulate cells, growth factors, and bioactive molecules while providing mechanical support during tissue regeneration positions them as a cornerstone of modern regenerative therapies. This article explores the preparation strategies, classification, applications, and future directions of injectable hydrogels in tissue engineering, emphasizing their transformative potential in addressing critical clinical challenges.

Preparation and Classification of Injectable Hydrogels

Injectable hydrogels are broadly classified into chemically crosslinked and physically crosslinked systems, each with distinct mechanisms and advantages.

Chemically Crosslinked Hydrogels

  1. Crosslinking Agent-Mediated Systems
    These hydrogels rely on covalent bonding between polymer chains using crosslinking agents. Glutaraldehyde (GTA) and genipin are widely employed due to their ability to enhance tensile properties. For instance, GTA reacts with functional groups in proteins and carbohydrates, forming stable networks. However, concerns over cytotoxicity drive the exploration of alternatives like genipin, a natural crosslinker with lower toxicity. Natural polymers (e.g., collagen, chitosan) and synthetic polymers (e.g., polyethylene glycol) are commonly used, with modifications to improve biocompatibility and degradation rates.

  2. High-Energy Radiation Crosslinking
    Gamma or electron beam irradiation facilitates crosslinking without chemical agents, enabling hydrogel formation at physiological pH and room temperature. While advantageous for avoiding toxic residues, radiation exposure limits in vivo applications due to potential cellular damage.

  3. Free Radical Polymerization
    Hydrophilic polymers functionalized with vinyl or acrylate groups undergo radical polymerization to form hydrogels. This method allows precise control over network density and mechanical properties, though initiator residues require careful purification.

  4. Enzymatic Crosslinking
    Enzymes such as horseradish peroxidase (HRP) and tyrosinase enable mild, site-specific crosslinking. For example, gelatin–poly(ethylene glycol)-tyramine (GPT) hydrogels crosslinked via HRP exhibit excellent bioactivity for cell encapsulation and tissue integration. Dual-enzyme systems (e.g., HRP and tyrosinase) further enhance tissue adhesion and mechanical stability.

Physically Crosslinked Hydrogels

Physical crosslinking relies on non-covalent interactions, offering reversible gelation and reduced cytotoxicity:

  • Ionic Interactions: Alginate-Ca²⁺ hydrogels form under physiological conditions, ideal for cell delivery.
  • Hydrophobic Interactions: Modified polysaccharides (e.g., hydrophobized dextran or chitosan) self-assemble into micellar networks, swelling upon water uptake.
  • Protein Interactions: Silk-elastin-like polymers (e.g., Prolastin®) undergo irreversible sol-gel transitions via crystallization of silk-like domains, enabling sustained drug release.

Applications in Tissue Regeneration

Angiogenesis

Vascularization remains a critical bottleneck in tissue engineering. Injectable hydrogels loaded with angiogenic factors (e.g., vascular endothelial growth factor [VEGF], basic fibroblast growth factor [bFGF]) localize delivery to ischemic or damaged tissues. Ishihara et al. demonstrated a photo-crosslinkable chitosan hydrogel (Az-CH-LA) incorporating paclitaxel and bFGF, which suppressed tumor growth while promoting neovascularization in murine models. Such systems balance anti-tumor and pro-angiogenic effects, highlighting dual functionality.

Bone Repair

Injectable hydrogels address irregular bone defects by conforming to complex shapes and delivering osteogenic factors. Vishnu Priya et al. developed a chitin/poly(butylene succinate) hydrogel loaded with fibrin nanoparticles and magnesium-doped bioglass. This composite induced early osteogenic differentiation, evidenced by upregulated alkaline phosphatase (ALP) and osteocalcin expression. Similarly, Vo et al. designed an N-isopropylacrylamide/gelatin microparticle hydrogel that enhanced mineralization and bony bridging at implant interfaces. Huang et al. reported a nanohydroxyapatite/glycol chitosan/hyaluronic acid hydrogel supporting MC-3T3-E1 cell adhesion and proliferation, underscoring its potential for craniofacial or spinal regeneration.

Cartilage Regeneration

Articular cartilage’s limited self-repair capacity demands innovative solutions. Kinard et al. utilized oligo(poly(ethylene glycol) fumarate) hydrogels to deliver chondrocytes and growth factors, achieving glycosaminoglycan (GAG) production comparable to native cartilage. Park et al. engineered a methacrylated glycol chitosan/hyaluronic acid hydrogel crosslinked via UV light, which enhanced chondrocyte proliferation and homogeneous GAG distribution. These systems emphasize the importance of tunable crosslinking density to mimic cartilage’s viscoelastic properties.

Key Design Considerations for Injectable Hydrogels

  1. Structural and Mechanical Compatibility
    Hydrogels must replicate the ECM’s 3D architecture to support cell adhesion, migration, and differentiation. Porosity and pore interconnectivity are critical for nutrient diffusion and vascular infiltration, particularly in pre-vascularized systems. For bone scaffolds, macroporosity (>100 µm) facilitates osteoblast infiltration and mineralization.

  2. Bioactive Molecule Delivery
    Sustained release of growth factors (e.g., BMP-2, TGF-β) enhances tissue-specific regeneration. However, burst release and denaturation remain challenges. Strategies like heparin-binding domains or nanoparticle encapsulation improve stability and controlled release.

  3. Degradation Dynamics
    Hydrogel degradation must synchronize with neotissue formation. Slow degradation impedes ECM remodeling, while rapid degradation compromises mechanical integrity. Enzymatically cleavable linkers (e.g., matrix metalloproteinase-sensitive peptides) offer spatiotemporal control.

  4. Clinical Translation
    Scalable synthesis under Good Manufacturing Practice (GMP) standards, long-term biocompatibility, and sterilization methods (e.g., gamma irradiation) are vital for regulatory approval. Preclinical models must replicate human biomechanics, particularly for load-bearing tissues like bone and cartilage.

Future Perspectives

Advancements in material science and biofabrication will drive the next generation of injectable hydrogels:

  • Multifunctional Systems: Integrating antimicrobial agents, immunomodulators, and conductive nanoparticles (e.g., graphene) could address infection, inflammation, and electrical signaling in cardiac or neural tissues.
  • 4D Printing: Spatiotemporal control over gelation and shape-memory properties enables dynamic adaptation to physiological changes.
  • Personalized Implants: Patient-specific hydrogels tailored via 3D bioprinting or in situ imaging (e.g., MRI-guided injection) promise precision medicine for complex defects.

In conclusion, injectable hydrogels represent a paradigm shift in tissue engineering, blending minimally invasive delivery with biomimetic functionality. Overcoming current limitations in vascularization, mechanical resilience, and translational workflows will unlock their full potential in regenerative medicine.

doi.org/10.1097/CM9.0000000000001055

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