Injectable Composite Systems Based on Microparticles in Hydrogels for Bioactive Cargo Controlled Delivery
Abstract
:1. Introduction
2. Microparticles in Hydrogel Systems
2.1. Gelation/Cross-Linking of the System
2.1.1. In Situ Gelation
2.1.2. Gelation before Injection
2.2. Microparticle Mixture with the Hydrogel
2.3. Particle Release: Mesh Pore Size and Degradation of the Matrix
2.4. Surface Charge and Hydrophobicity of the Polymers
2.5. Rheological Properties
2.6. Swelling
3. Microparticles in Hydrogel Systems as DDS
3.1. Controllable Drug/Bioactive Agents Release Rate
3.2. In Loco Stability and Drug Release
3.3. Sequential Release and Co Delivery
3.4. Encapsulation of Hydrophobic Drugs
4. Fields of Application
4.1. Cancer Treatment
4.2. Cardiovascular Diseases
4.3. Spinal Diseases
4.4. Cartilage
4.5. Bone
4.6. Skin
4.7. Other
4.8. Tissue Engineering
5. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Microparticles | Hydrogels | Bioactive Cargo | Observations | Ref. |
---|---|---|---|---|
PLGA | PLAF-b- PEG-b- PLA | Combretastatin A-4 and docetaxel | Sequential release of drugs. The synergistic system suppressed the spread of an osteosarcoma in in vivo tests. | [14] |
PCL–PEG–PCL | PCL–PEG–PCL | Camptothecine | The composite system had a strong anti-tumour effect. The system suppressed growth and metastasis in in vivo tests. | [17] |
Double walled microparticles with PLGA and PDLLA | Aldehyde functionalized sodium alginate | Cisplatin and paclitaxel | Beyond the use for chemotherapeutics the hydrogel of the system also served as an antibacterial agent, due to the presence of polyethyleneimine within the hydrogel. | [49] |
PLGA | Pluronic and copolymer of PEG-PCL-PLLA | DOX and 5 FU | Microparticles carried DOX and the hydrogel carried 5 FU. Pluronic rapidly cleared whilst the copolymer endured. The spread of the drug to healthy tissues was not observed in vivo. | [52] |
PCL–PEG–PCL | Hyaluronic acid | 5 FU, cisplatin and paclitaxel | Hydrogel loaded with 5Fu and cisplatin and microspheres with paclitaxel. Both evaluated separately. Good in vivo performance. | [54] |
PCL | Alginate | DOX and ibuprofen | Early release of ibuprofen as an anti-inflammatory agent followed by DOX release for cytotoxic effect. | [55] |
Vaterite microspheres | Silk nanofibers | DOX | Several combinations made. The system significantly decreased viability of MCF-7 cells in in vivo tests. | [56] |
PLGA | PEG and PNIPAAm conjugates | Camptothecin and vincristine | Drugs loaded only on the microparticles. Vincristine had a better performance than camptothecin, with longer rates of survival. | [57] |
Gelatine | Alginate and chitosan | 5 FU and iron oxide nanoparticles | Under an external magnetic field, the system released higher quantities of 5 FU for higher times but had no effect in the initial release. | [58] |
Microparticles | Hydrogels | Bioactive Cargo | Observations | Ref. |
---|---|---|---|---|
Silk fibroin | Alginate | IGF-1 | After 28 days microspheres in hydrogel system with IGF-1 had the higher enhancement in cardiac function. | [21] |
PLLA-PEG-PNIPAAm | PLLA-PEG-PNIPAAm | Stem cells | Copolymer assembled into microspheres. PNIPAAm branch served has physical links that formed a hydrogel in the presence of water. | [26] |
Silk fibroin | Alginate | VEGF and BMP9 | Sequential release of two bioactive agents. VEGF was loaded to the hydrogel (for rapid release) and BMP9 to the microparticles (for prolonged release). | [42] |
Albumin | Silk fibroin and PEGDA | Stem cells | In vitro 3D cell culture revealed proteins characteristic of early cardiac muscle cell differentiation. | [60] |
PLGA | Poly (NIPAAm-co-HEMA-co-MAPLA) copolymer | IGF-1 and bFGF | In vivo presence of growth factors was high but no improvements to cardiac functions were noted. | [61] |
Protein coated PLGA | Based-hyaluronic acid | Stem cells | Formation of functionalized mesenchymal stem cell aggregates for the delivery of bioactive factors with the protection of hyaluronic acid hydrogel. | [62] |
Microparticles | Hydrogels | Bioactive Cargo | Observations | Ref. |
---|---|---|---|---|
PLGA with tannic acid | Oxidized dextran and hyaluronic acid-hydrazide | BDNF | Tannic acid increased electrical conductivity and mechanical properties. | [15] |
Gelatine | Collagen-low molecular weight hyaluronic acid | TGF-b3 | The hydrogels supported growth and differentiation of MSC. Microparticles delivered TGF-b3 that promoted cell differentiation. | [32] |
Gelatine | Hyaluronic acid and N-isopropylacrylamide | Epigallocatechin 3-gallate | Reduction of inflammatory response with efficient drug encapsulation with electrospraying. | [44] |
PLGA | Alginate | Minocycline hydrochloride and paclitaxel | Co-delivery of drugs. MH regulated the inflammatory process and PTX promoted tissue regeneration and decreased scar tissue. | [63] |
PLGA | Hyaluronic acid and methylcellulose | Brain-derived neurotrophic factor (BDNF) | The composite system had a more controlled release of BDNF compared to the hydrogel alone. | [64] |
Microparticles | Hydrogels | Bioactive Cargo | Observations | Ref. |
---|---|---|---|---|
Chitosan | Oxidized alginate and carboxymethyl chitosan | Melatonin and methylprednisolone | Melatonin conjugated with chitosan. Tripolyphosphate was used to develop microspheres loaded with methylprednisolone. In vivo tests compared the effect of hydrogel alone and microparticles in hydrogel system. The latter had the best cartilage regeneration. | [66] |
Alginate sulphate | Alginate and PVA | PRP and Rabbit adipose-derived mesenchymal stem cells | Sustained release of PRP to the hydrogel carrying stem cells had a significant gene expression compared with the hydrogel with free PRP. | [67] |
PLGA | Gelatine methacryloyl | Kartogenin and curcumin | Microparticles loaded with kartogenin were incorporated within MSC aggregates to promote chondrocyte differentiation and the hydrogel served has a scaffold with curcumin to moderate inflammatory response. | [68] |
PLGA | Chitosan and gelatine | Stromal cell-derived factor-1 | Injectable hydrogel for recovery of osteochondral tissue regeneration. The microparticles in hydrogel system had a prolonged release profile and promoted the cartilage regeneration. | [69] |
PCL-PEG-PCL | Alginate and PVA | Calcium gluconate | Calcium gluconate served as an in situ cross-linking solution for the alginate hydrogel. | [70] |
Microparticles | Hydrogels | Bioactive Cargo | Observations | Ref. |
---|---|---|---|---|
Hydroxyapatite | Alginate | Strontium | Strontium presence increased the bone formation. Only local delivery occurred. | [40] |
Bioglass | PVA | BMP2 and VEGF | Increase in mechanical properties. In vivo tests revealed that the microparticles in hydrogel system is more efficient than bulk hydrogel to treat bone defects. | [71] |
Chitosan | Methyl cellulose and alginate | BMP2 and VEGF | VEGF was loaded to the hydrogel and BMP within the particles. VEGF had a faster release when compared to BMP2. | [72] |
PLGA | Alginate | BMP2 and VEGF | Injectable composite system for sequential delivery of bioactive factors for vascularization and bone regeneration. In vivo, the system induced vascularization and ectopic bone formation. | [73] |
PLGA and hydroxyapatite | Chitosan | BMP2 and VEGF | After 12 weeks, the delivery of BMP2 and the co delivery of both agents using the composite system promoted a complete healing of the bone defect. | [74] |
Biphasic calcium phosphate | Hyaluronic acid and chitosan | Adipose-derived stem cells and platelet rich plasma | Development of a thermoresponsive microparticles in hydrogel system. Improvement of cell proliferation and mineralization of extracellular matrix. | [75] |
Alginate and chitosan/PLA/alginate | Chitosan and glycerophosphate | BMP2 and platelet-derived growth factor-BB | Sequential release with encapsulation in different microparticles. Release patterns regulated by the number of microparticles embedded in the hydrogel and the initial drug load in microparticles. | [76] |
PLGA and PLA | Chitosan and collagen | BMP2 and 17β-estradiol | Presence of hydroxyapatite diminished burst effect on PLGA microspheres with BMP2. Results suggested that 17β-estradiol had no effect on bone regeneration. | [77] |
PLGA and PLA-S | Poloxamine (T-1307) and alginate | BMP2, platelet rich growth factors and 17β-oestradiol | Alginate increased viscosity and diminished the gelation temperature of poloxamine. Microparticles increased viscosity. Drug release had an early fast release followed by a prolonged slow released to up 6 weeks. | [78] |
CaCO3 | Fibrin-glue | BMP2 | Within 8 weeks in vivo in tibia bone defects of rabbits, the composite system had nearly healed the defects. | [79] |
Gelatine | Synthetical polymers | Mesenchymal stem cells | Gelatine microparticles served as porogens for the hydrogel to promote cell attachment and proliferation. | [80] |
Calcium carbonate microparticles and hydroxyapatite nanoparticles | Chitosan and alginate | Tetracycline hydrochloride | Hydroxyapatite and microparticles ratio affected mechanical properties. Sustained release and antibacterial properties were observed. | [81] |
Microparticles | Hydrogels | Bioactive Cargo | Observations | Ref. |
---|---|---|---|---|
PLGA and alginate | Alginate and bioglass | Condition medium of RAW 246.7 cells and pirfenidone | Sequential release that accompanies the different stages of wound healing, with specific agents for each one. | [41] |
Alginate | Oxidized alginate and N-succinyl chitosan | Bull Serum Albumin | Higher compressive modulus and slower release profiles compared with the hydrogel and microparticles alone. | [82] |
PLGA | Aminated gelatine, adipic acid dihydrazyde and oxidized dextran | Chlorhexidine acetate and basic fibroblast growth factor (bFGF) | Self-healing hydrogel with antibacterial properties and sequential delivery. Chlorhexidine acetate would serve as an antibacterial agent for an early release, followed by a latter release of bFGF for cell proliferation. | [83] |
PLGA | Chitosan | Platelet-derived growth factor receptor | Promotion of granulation formation and collagen deposition with the microparticles in hydrogel system. | [84] |
Hydroxyapatite | Hyaluronic acid | None | Application for rejuvenation of aged skin. Viscosity and storage modulus increased with hydroxyapatite microparticles presence. | [85] |
PDLLA | Collagen | Fibroblasts | Porous PDLLA microspheres served as scaffolds for cell adhesion | [86] |
Treatment Objective | Microparticles | Hydrogels | Bioactive Cargo | Observations | Ref. |
---|---|---|---|---|---|
Diabetes | PLGA-based | Dopamine-conjugated hyaluronic acid | Insulin | Glucose-regulated insulin delivery system. With a single administration, stabilized glucose’s level for 2 weeks in vivo. | [22] |
Post-operative ocular system | PLA | Triblock polymers | Fluoroquinolone moxifloxacin, dexamethasone, and beta-blocker levo-bunolol | Different triblock polymers were studied. Hydrophobicity used to regulate the delivery profile and to delay the initial burst. | [31] |
Macular degeneration | PLGA | PNIPAAm | Anti-VEGF | Prolonged drug delivery. In vitro release prolonged for about 200 days. | [39] |
Macular degeneration | PLGA | PNIPAAm | Anti-VEGF | The microparticles in hydrogel system decreased the ocular lesion areas in vivo. | [87] |
Periodontitis | PLGA | Polyisocyanopeptide | Doxycycline and lipoxin | Ester capped PLGA microparticles had a longer release profile than the acid terminated ones | [88] |
Periodontitis | PLGA | Gelatine | Simvastatin | Controlled release of simvastatin for tooth extraction. The microparticles in hydrogel system promoted bone formation after 5 weeks. | [89] |
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Carrêlo, H.; Soares, P.I.P.; Borges, J.P.; Cidade, M.T. Injectable Composite Systems Based on Microparticles in Hydrogels for Bioactive Cargo Controlled Delivery. Gels 2021, 7, 147. https://doi.org/10.3390/gels7030147
Carrêlo H, Soares PIP, Borges JP, Cidade MT. Injectable Composite Systems Based on Microparticles in Hydrogels for Bioactive Cargo Controlled Delivery. Gels. 2021; 7(3):147. https://doi.org/10.3390/gels7030147
Chicago/Turabian StyleCarrêlo, Henrique, Paula I. P. Soares, João Paulo Borges, and Maria Teresa Cidade. 2021. "Injectable Composite Systems Based on Microparticles in Hydrogels for Bioactive Cargo Controlled Delivery" Gels 7, no. 3: 147. https://doi.org/10.3390/gels7030147