Poly(N-isopropylacrylamide)-Based Hydrogels for Biomedical Applications: A Review of the State-of-the-Art

Abstract

A prominent research topic in contemporary advanced functional materials science is the production of smart materials based on polymers that may independently adjust their physical and/or chemical characteristics when subjected to external stimuli. Smart hydrogels based on poly(N-isopropylacrylamide) (PNIPAM) demonstrate distinct thermoresponsive features close to a lower critical solution temperature (LCST) that enhance their capability in various biomedical applications such as drug delivery, tissue engineering, and wound dressings. Nevertheless, they have intrinsic shortcomings such as poor mechanical properties, limited loading capacity of actives, and poor biodegradability. Formulation of PNIPAM with diverse functional constituents to develop hydrogel composites is an efficient scheme to overcome these defects, which can significantly help for practicable application. This review reports on the latest developments in functional PNIPAM-based smart hydrogels for various biomedical applications. The first section describes the properties of PNIPAM-based hydrogels, followed by potential applications in diverse fields. Ultimately, this review summarizes the challenges and opportunities in this emerging area of research and development concerning this fascinating polymer-based system deep-rooted in chemistry and material science.

Keywords: PNIPAM; drug delivery; hydrogels; smart polymer; tissue engineering; wound healing.

Figure 1

Physical and chemical crosslinking methods to prepare hydrogel systems for biomedical application [128].

Figure 2

(A) SEM images of (a) Gel 1; (b) Gel 2; (c) Gel 3; (d) Gel 4; (e) Gel 5; (f,g) Gel 6; (h) Gel 7; and (i) Gel 8. (B) DSC analysis of gel phase transition characteristics. (C) (a) Temperature-dependent swelling ratios of gels between 20 and 50 degrees Celsius; (b) gel deswelling behavior at 60 degrees Celsius. (D) The simulated release curves and release behaviors of 5-FU from gels in PBS (pH 7.4) at 37 °C [177].

Figure 3

(A) SEM structural analysis of Alg-g-P (NIPAAm) hydrogels premised on (a) Algogel3001, (b) Algogel6021, (c) Satialgine S60NS, (d) SatialgineS900NS, (e) Sigma, and (f) XPU alginate. (B) As a pDNA and RALA/pDNA NPs delivery device, Alg-g-PNIPAM hydrogel was used. (a) For up to one month in DDW at 37 °C, hydrogels discharged pDNA (continuous line) at a faster rate (burst release) than RALA/pDNA NPs (dashed line). (b) DNA stability was sustained in algogel 3001-g-P (NIPAAm) hydrogels for uncomplexed pDNA for up to 10 days and complexed RALA NPs for up to 30 days; * p  < 0.05. (C) Degradation of algogel 3001-g-PNIPAM hydrogel at 70 °C in cell medium for 3 days caused cytotoxicity in PC3 and MG63 cells. (D) Evaluation of DNA transfection effectiveness after 15 days of incubation in Alg-g-PNIPAM hydrogel (A) flow cytometry analysis for transfection efficiency (B) The prevalence of green fluorescent protein-expressing cells for the various treatment groups. Reproduced with permission from [211], copyright Elsevier, 2017.

Figure 4

(a) The cytocompatibility and cell survival of rADSCs were improved by HA-modified PNIPAM hydrogels. Using (A) live and dead staining and (B) an MTS assay, cell survival of rADSCs encapsulated in PNIPAM, HA-PNIPAM-CP, and HA-PNIPAM-CL hydrogels was determined during days 1 and 5. (b) In rADSCs cultivated in PNIPAM, HA-PNIPAM-CP, and HA-PNIPAM-CL hydrogels for 1, 3, 5, and 7 days, the chondrogenic indicators of gene expression of (A) type II collagen and (B) aggrecan were detected. Collagen type II and aggrecan mRNA expression levels in rADSCs cultivated in HA-modified hydrogels are expressed and normalized in comparison to rADSCs cultured in PNIPAM hydrogels, which is designated as 1. (c) At days 5 and 7, there was enhanced cell aggregation and cartilaginous matrix sGAG production in rADSC cultured HA-modified PNIPAM hydrogels in vitro. (A) Glycosaminoglycans stained with Alcian blue (sGAG). (B) The DMMB assay was used to quantify the production of sGAG. (d) In vivo evaluation of the increase of neocartilage development in rADSCs/HA- PNIPAM-CL constructions using a rabbit model. (A) Illustration of the intraarticular injection of the rADSC/hydrogel constructions into the synovial cavity of rabbit knees. After 3 weeks, injected rADSC/hydrogel constructions were collected from rabbit synovial cavities and analyzed using (B) H&E staining, (C) confocal microscopy for pictures of bright fields, and CM-DiI-labeled rADSCs (red, arrows), (D) safranin-O fast green staining showing sGAG deposition (arrows), and (E) IHC staining for type II collagen synthesis (brown). Normalized relative to the PNIPAM group, which is defined as 1. Quantification examination of safranin-O staining (F) and type II collagen staining (G). Scale bar: 100 μm. (*), (**), and (***) represented p  <  0.05, p  <  0.01, and p < 0.005 respectively, in contrast with the PNIPAM group. (^#), and (^##) represented p < 0.05, and p  <  0.01, respectively in contrast with the HA-PNIPAM-CP group [226].

Figure 5

(a) Effective burst release of tPA is indicated by cumulative tPA release from C/S nanogels (A) and examination of fibrinolysis in the existence of drug-loaded nanogels (B). (b) The expression of fibrotic markers such as -SMA and CTGF on neonatal rat cardiac fibroblasts is reduced by introducing drug-loaded C/S particles in vitro (A). Percentage of stress fiber-positive cells for -SMA and adjusted total cell fluorescence for CTGF were used to quantify the results (B). (c) In vitro, FSNs adhere to and are maintained at fibrin clot borders at 1 sec-1 wall shear rates. A fibrin clot (green) was polymerized along the channel using PDMS molds (A). Particle binding (red) throughout 20 min and retention (C) during a 20 min buffer wash demonstrate deposition at fibrin clot sites, as measured by fluorescence intensity at the clot boundary (B). (d) In vivo dual-loaded FSNs augment left ventricular ejection fraction 2 and 4 weeks after I/R (A). Dual-loaded FSNs dramatically reduce infarct size (B) 4 weeks after damage, as measured by Masson’s trichrome staining and measuring blue collagen stain as a percent of the left ventricular area (C). Four weeks after I/R (D), dual-loaded FSNs significantly reduce -SMA (top, green) and CTGF (bottom, red) expression in vivo, as measured by immunofluorescence intensity (E). (*), (**), (***), and (****) represented p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively. Reproduced with permission from [248], copyright ACS, 2018.

Figure 6

(A) The synthesis of thermoresponsive poly(N-isopropylacrylamide) (PNIPAM)-cellulose nanocrystal (CNC) hybrid hydrogels and a graphic depiction of the structural framework of drug release and drug load. (B) Thermoresponsive characteristics of PNIPAM-CNC hybrid hydrogels: (a) volume phase transition temperature (VPTT) profiles of hydrogels NC-0, NC-50+, NC-50, NC-20, NC-10, NC-5, and NC-1, with temperatures of 32, 34, 36.2, 37.5, 38.5, 39, and 39 degrees Celsius, correspondingly; (b) equilibrium swelling ratio (ESR) of PNIPAM-CNC hybrid hydrogels at various temperatures. (C) TGA thermograms of a pure CNC sample and produced PNIPAM-CNC hybrid hydrogels with varied levels of CNC content revealing thermal degradation characteristics. (D) Metronidazole (MZ) release profile from NC-50 hydrogels in phosphate-buffered saline (PBS) with pH 7.4 at 37 °C in vitro [142].