Hydrogel and Its Medical Applications

Hydrogels have been used as one of the most common tissue engineering scaffolds over the past two decades.  They are a unique group of biocompatible 3D polymeric substances which can act as a scaffold and mimic the properties of various tissues in the body. Due to their ability to retain high water content, maintain porous structure, and adapt by interchangeable sol-gel conditions, hydrogels can:^[1]

• Provide an ideal environment for cell survival, and structure which mimics the native tissues
• Serve as a supportive matrix for cell immobilization and growth factor delivery

The mechanism is by

• Incorporating cells in their structure while eventually degrading themselves to leave behind only healthy tissue
• Promoting the influx of cell metabolites and the disposal of cell wastes through their pores.

With consistent efforts, researchers have strived to engineer these hydrogels by modifying their physical and chemical properties, referring to them as ‘smart’ or ‘intelligent’ hydrogels since they respond to external stimuli like temperature, pH, light, magnetic and electric fields, ionic strength, or enzymatic environment.^[5]

Different Applications

Smart hydrogels have shown great potential in non-invasive, remote-controlled therapies, including:

• Targeted drug delivery^[6-9]
• Regenerative medicine^[10,11]
• Tissue engineering^[12-15]
• Implanting artificial organs^[16,17]

Figure 1.  Schematic diagram for the development of targeted nanoparticles^[18]

Targeted Drug Delivery

Biodegradable nanoparticles formulated from different polymeric substances:

• Poly (d,l-lactide-co-glycolide) (PLGA) 
• In [6], it demonstrated rapid escape of PLGA nanoparticles from the endo-lysosomal compartment into cytosol following their uptake.  Based on the above mechanism, various potential applications of nanoparticles for delivery of therapeutic agents to the cells and tissue are considered.
• A commercially available drug delivery device using PLGA is Lupron Depot for the treatment of advanced prostate cancer.
• Hydrogel^[7,20]
• Hydrogel nanoparticles have gained considerable attention in recent years as one of the most promising nanoparticulate drug delivery systems owing to their unique potentials via combining the characteristics of a hydrogel system (e.g., hydrophilicity and extremely high water content) with a nanoparticle (e.g., very small size).  
• Among the natural polymers, chitosan and alginate have been studied extensively for preparation of hydrogel nanoparticles and from synthetic group, hydrogel nanoparticles based on poly (vinyl alcohol), poly (ethylene oxide), poly (ethyleneimine), poly (vinyl pyrrolidone), and poly-N-isopropylacrylamide have been reported with different characteristics and features with respect to drug delivery.

have been extensively investigated for sustained and targeted/localized delivery of different agents including:

• Plasmid DNA
• Proteins and peptides 
• Low molecular weight compounds

Several researches have been done recently about:

• The mechanism of intracellular uptake of nanoparticles
• Their trafficking and sorting into different intracellular compartments
• The mechanism of enhanced therapeutic efficacy of nanoparticle-encapsulated agent at cellular level

Peripheral Nerve Regeneration

Alginate may be used in a hydrogel consisting of microparticles or bulk gels combined with nerve growth factor in bioengineering research to stimulate brain tissue for possible regeneration.^[2]

In [4], the heparin/collagen encapsulating nerve growth factor (NGF) multilayers were coated onto the aligned poly-L-lactide (PLLA) nanofibrous scaffolds via a layer-by-layer (LbL) self-assembly technique to combine biomolecular signals, and physical guidance cues for peripheral nerve regeneration.

Bone Tissue Engineering

Alginate, an anionic polymer owing enormous biomedical applications, is gaining importance particularly in bone tissue engineering due to its biocompatibility and gel forming properties. Several composites such as:^[3]

• Alginate-polymer (PLGA, PEG and chitosan)
• Alginate-protein (collagen and gelatin)
• Alginate-ceramic
• Alginate-bioglass
• Alginate-biosilica
• Alginate-bone morphogenetic protein-2
• RGD peptides composite 

have been investigated till date. 

These alginate composites show enhanced biochemical significance in terms of porosity, mechanical strength, cell adhesion, biocompatibility, cell proliferation, alkaline phosphatase increase, excellent mineralization and osteogenic differentiation. Hence, alginate based composite biomaterials will be promising for bone tissue regeneration.

References

1. Smart Hydrogels in Tissue Engineering and Regenerative Medicine
2. Büyüköz, M.; Erdal, E.; Altinkaya, S.A. (2016). "Nanofibrous gelatin scaffolds integrated with NGF-loaded alginate microspheres for brain tissue engineering". J. Tissue Eng. Regen. Med. 12 (2): e707–e719.
3. Venkatesan, J; Bhatnagar, I; Manivasagan, P; Kang, K. H.; Kim, S. K. (2015). "Alginate composites for bone tissue engineering: A review". International Journal of Biological Macromolecules. 72: 269–81. 
4. Heparin/collagen encapsulating nerve growth factor multilayers coated aligned PLLA nanofibrous scaffolds for nerve tissue engineering
5. Bacelar A.H., Cengiz I.F., Silva-Correia J., Sousa R.A., Oliveira J.M., Reis R.L. Handbook of Intelligent Scaffolds for Tissue Engineering and Regenerative Medicine. 2nd ed. Pan Stanford Publishing Pte. Ltd.; Singapore: 2017. “Smart” hydrogels in tissue engineering and regenerative medicine applications; pp. 333–364.
6. Panyam J., Labhasetwar V. Biodegradable nanoparticles for drug and gene delivery to cells and tissue. Adv. Drug Deliv. Rev. 2012 .
7. Hamidi M., Azadi A., Rafiei P. Hydrogel nanoparticles in drug delivery. Adv. Drug Deliv. Rev. 2008;60:1638–1649.
8. Uhrich K.E., Cannizzaro S.M., Langer R.S., Shakesheff K.M. Polymeric Systems for Controlled Drug Release. Chem. Rev. 1999;99:3181–3198.
9. Langer R. New methods of drug delivery. Science. 1990;249:1527–1533.
10. Slaughter B.V., Khurshid S.S., Fisher O.Z. Hydrogels in regenerative medicine. Adv. Mater. 2009;21:32–33. doi: 10.1002/adma.200802106.
11. Bettinger C., Borenstein J., Langer R. Nanotechnology and Regenerative Engineering. CRC Press; Boca Raton, FL, USA: 2014. Microfabrication techniques in scaffold development; pp. 103–142.
12. Lee K.Y., Mooney D. Hydrogels for tissue engineering. Am. Chem. Soc. Chem. Rev. 2001;101:1869–1880.
13. Drury J.L., Mooney D.J. Hydrogels for tissue engineering: Scaffold design variables and applications. Biomaterials. 2003;24:4337–4351.
14. Khademhosseini A., Langer R. A decade of progress in tissue engineering. Nat. Protoc. 2016;11:1775–1781.
15. Leijten J., Seo J., Yue K., Trujillo-de Santiago G., Tamayol A., Ruiz-Esparza G.U., Khademhosseini A., Shin S.R., Sharifi R., Noshadi I., et al. Spatially and temporally controlled hydrogels for tissue engineering. Mater. Sci. Eng. R Rep. 2017;119:1–35.
16. Ratner B.D., Hoffman A.S. Synthetic Hydrogels for Biomedical Applications. Hydrogels Med. Relat. Appl. 1976;31:1–36.
17. Burczak K., Gamian E., Kochman A. Long-term in vivo performance and biocompatibility of poly(vinyl alcohol) hydrogel microcapsules for hybrid-type artificial pancreas. Biomaterials. 1996;17:2351–2356.
18. Nanoparticulate Drug Delivery System
19. Designing hydrogels for controlled drug delivery
20. Development and functional characterization of alginate dressing as potential protein delivery system for wound healing