Elsevier

Journal of Controlled Release

Volume 329, 10 January 2021, Pages 16-35
Journal of Controlled Release

Review article
Injectable thermoresponsive hydrogels as drug delivery system for the treatment of central nervous system disorders: A review

https://doi.org/10.1016/j.jconrel.2020.11.049Get rights and content
Under a Creative Commons license
open access

Highlights

  • Thermoresponsive hydrogels represent a possible approach to overcome limitations of central nervous system drug delivery

  • Thermoresponsive hydrogels are liquid at room temperature and turn into a stable gel at body temperature

  • Thermoresponsive hydrogels can be non-invasively administered in the central nervous system without any invasive surgery.

  • Thermoresponsive hydrogels can be used as a local depot for prolonged and sustained release of therapeutic agents

Abstract

The central nervous system (CNS), consisting of the brain, spinal cord, and retina, superintends to the acquisition, integration and processing of peripheral information to properly coordinate the activities of the whole body. Neurodegenerative and neurodevelopmental disorders, trauma, stroke, and brain tumors can dramatically affect CNS functions resulting in serious and life-long disabilities. Globally, the societal and economic burden associated with CNS disorders continues to grow with the ageing of the population thus demanding for more effective and definitive treatments.

Despite the variety of clinically available therapeutic molecules, medical interventions on CNS disorders are mostly limited to treat symptoms rather than halting or reversing disease progression. This is attributed to the complexity of the underlying disease mechanisms as well as to the unique biological microenvironment. Given its central importance, multiple barriers, including the blood brain barrier and the blood cerebrospinal fluid barrier, protect the CNS from external agents. This limits the access of drug molecules to the CNS thus contributing to the modest therapeutic successes.

Loco-regional therapies based on the deposition of thermoresponsive hydrogels loaded with therapeutic agents and cells are receiving much attention as an alternative and potentially more effective approach to manage CNS disorders. In this work, the current understanding and challenges in the design of thermoresponsive hydrogels for CNS therapy are reviewed. First, the biological barriers that hinder mass and drug transport to the CNS are described, highlighting the distinct features of each barrier. Then, the realization, characterization and biomedical application of natural and synthetic thermoresponsive hydrogels are critically presented. Advantages and limitations of each design and application are discussed with the objective of identifying general rules that could enhance the effective translation of thermoresponsive hydrogel-based therapies for the treatment of CNS disorders.

Keywords

Injectable gels
Drug delivery system
Neurological disorders
Brain cancer
Polymer design

Abbreviations

AD
Alzheimer's disease
aFGF
acidic fibroblast growth factor
AIBA
2,2′-azobis [2-methylpropionamide] dihydrochloride
BBB
blood brain barrier
BBTB
blood brain tumor barrier
BCSFB
blood cerebrospinal fluid barrier
BDNF
brain-derived neurotrophilc factor
bFGF
basic fibroblast growth factor
BMA
butylmethacrylate
BSA
bovine serum albumin
CED
convention enhanced delivery
CMC
carboxymethylcellulose
CNS
central nervous system
CSF
cerebrospinal fluid
DFO
deferoxamine mesylate
DOX
doxorubicin
DPSC
dental pulp stem cells
DSC
differential scanning calorimetry
dscECM
descellularized spinal cord extracellular matrix
ECM
extracellular matrix
EGF
epidermal growth factor
EMA
European Medicine Agency
EPO
erythropoietin
FGF-2
fibroblast growth factor-2
FUS
focused ultrasound
G'
storage modulus
G"
loss modulus
GBM
glioblastoma
GDNF
glial-derived neurotrophic factor
GF
growth factor
HA
hyaluronan
HP
heparin-poloxamer
ICV
intracerebroventricular
IP
intraperitoneal
IT-L
intrathecal-lumbar
LSCT
lower critical solution temperature
MC
methylcellulose
MFG-E8
milk fat globule-epidermal growth factor 8
MSC
mesenchymal stem cells
MSC
microsphere
NGF
nerve growth factor
NIPAAm
N-isopropylacrylamide
NP
nanoparticle
NSC
neural stem cells
NT-3
neurotrophin-3
PAA
poly(amidoamine)
Pcgel
PEG-g-chitosan
PCL
polycaprolactone
PD
Parkinson's disease
PEG
poly(ethylene glycol)
PEGMA
poly(ethylene glycol) methacrylate
PGRN
progranulin
PLA
poly(lactic acid)
PLGA
poly(lactic-co-glycolic acid)
pNIPAAm
poly(N-isopropylacrylamide)
PTX
paclitaxel
RNS
reactive nitrogen species
ROS
reactive oxygen species
SCI
spinal cord injury
TBI
traumatic brain injury
TGP
thermoreversible gelation polymer
TMZ
temozolomide
VEGF
vascular endothelial growth factor
ν
viscosity

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These authors share the senior authorship.