Hollow microgels and their hybrids: classification, synthesis, characterization, properties and applications

Abstract

Hollow microgels and their hybrids have gained much attention in modern-day research because of their fascinating properties and potential applications. This article gives classification, preparation methods, properties and applications of hollow microgels and their hybrids in modern research. Some of the hollow microgels and their hybrids respond to change in specific environmental stimuli like pH, ionic strength and temperature of the medium. They are called smart polymer hollow microgels and smart hybrid microgels, respectively. This peculiar behaviour makes them a suitable candidate for their use in drug delivery, sensing, catalysis and many other fields. This review represents the current advancement along with future perspectives and suggestions for further research in this particular area.

1. Introduction

The polymeric gels which show swelling in water are called hydrogels (Begum et al. 2016). When hydrogels are confined to submicron size range, they are categorized as microgels or nanogels (Pérez-Juste et al. 2013). But the hydrogels with extensive cross-linking and macroscopic network are referred as bulk hydrogels. Macrogels show extensively cross-linked structure, while microgels are basically colloidal dispersion of gel particles in a suitable solvent (Begum et al. 2016). The particles having a diameter of 0.1–100 μm are known as microgels (Begum et al. 2019). The soft polymeric particles have the same liquid in their sieves. One of the most interesting features of the microgels is their fast responsive behaviour towards external stimuli such as pH (Liu et al. 2011), temperature (Berndt et al. 2006), solvent composition (Keidel et al. 2018), glucose concentration (Lapeyre et al. 2008) and ionic strength (Zhang et al. 2015) of the medium. Due to their responsive behaviour towards external stimuli, microgels have gained much attention as potential candidates for biomedical (Guan and Zhang 2011), nano-technological (Pich et al. 2006), environmental (Begum et al. 2017) and catalytic (Shah et al. 2017) applications. Microgels can be classified into core–shell microgels (Dubbert et al. 2015) and hollow microgels (Scotti et al. 2018, 2021). Core–shell microgels are usually composed of soft outer shell and solid inner core (Nickel et al. 2019). Hollow microgel is one of the fascinating microgel systems which has some distinct features. Hollow microgels have a fuzzy shell surrounding a cavity filled with solvent (Dubbert et al. 2014; Schmid et al. 2016). Properties like deformability, permeability, uptake and release ability can be improved by altering cross-linking density of shell and by changing external stimuli. They possess a higher de-swelling ability than that of a regular homogeneous microgel system (Scotti et al. 2018). The presence of a cavity adds softness to microgels, because of their potential to adjust their size in a crowded environment. Furthermore, the replacement of interior part of microgel particle by solvent makes hollow microgel system, a different class of colloidal suspensions with unique and unexplored properties. Therefore, in last few decades, different approaches have been adopted to synthesize hollow microgels. Free radical precipitation polymerization (Nayak et al. 2005) and modification in core–shell microgels (Nickel et al. 2019) have been widely reported for fabrication of hollow microgel systems.

The hybridization of inorganic nanomaterial and smart microgels has become a subject of interest in last two decades due to existence of properties of both inorganic and organic components in a single fascinating system known as hybrid microgel (Arif et al. 2022a; Begum et al. 2017; Li et al. 2022). For example, Arif et al. (2022b) have reported the incorporation of silver and cobalt nanoparticles in poly(N-isopropylmethacrylamide) microgels and studied their catalytic applications. Similarly, Ambreen et al. (2022) have reported poly(N-vinylcaprolactam-co-acrylic acid) microgel loaded with silver nanoparticles. Various morphologies of microgels and their hybrids synthesized by different strategies have been reported for their potential applications in various fields (Begum et al. 2019; Karg 2012; Karg and Hellweg 2009a). Fabrication and stabilization of inorganic nanoparticles in hollow microgel system also has different strategies as reported in literature (He et al. 2015; Xie et al. 2009). Hollow microgels and their hybrids are considered as an advanced and appealing system for numerous applications, like drug delivery (Masoud and Alexeev 2012; Xing et al. 2011b), catalysis (Tripathi et al. 2014a), water filtration (Scotti et al. 2018), bio sensing (Chen et al. 2000) and chemical separation (Bergbreiter et al. 1998).

Various general reviews on smart microgels and hybrid microgels are available in literature (Karg and Hellweg 2009a, 2009b; Seiffert and Weitz 2010). Begum et al. (2016) have reviewed preparation, characterization and uses of smart microgels loaded with silver nanoparticles. Temperature sensitive hybrid microgels for catalysis have been reviewed by the same group (Farooqi et al. 2017). Karg et al. (2009b) have reviewed the synthesis and characterization of hybrid microgels. Farooqi et al. (2016) have also reviewed the smart microgels loaded with gold nanostructures. All above mentioned reviews have been written in general and cover all types of microgels and hybrid microgels. Hollow microgels and hollow hybrid microgels have gained substantial consideration because of their novel features like the presence of cavity or pit in hollow microgels filled with solution enables them to be used as support for nanoparticles, they offer increased active area for catalysis and the refractive index modulation by the void in hollow particles. But to the best of our knowledge, no one has reviewed recent research progress of these peculiar microgel systems.

This review presents advances in classification, preparation strategies, characterizations, properties and applications of hollow microgels and their hybrids.

2. Classification of hollow microgels and their hybrids

Hollow microgels can be categorized into different types in different ways. The following classification is based on responsive behaviour of hollow microgels, morphology of hollow microgels and type of material loaded to make hybrid hollow microgel systems.

2.1. On the basis of responsive behaviour

Hollow microgels and their hybrids can be classified on the basis of their response towards different stimuli such as temperature (Brugnoni et al. 2020; Contreras-Cáceres et al. 2015; Dubbert et al. 2015; Nayak et al. 2005), pH (Li et al. 2008a; Yang et al. 2009), ionic strength (Wypysek et al. 2020) and glucose concentration (Zhang et al. 2007) of the medium. Owing to this smart nature, the size of hollow microgel and hybrid microgel particles changes with change in an environmental stimulus. The detail of smart behaviour of these microgels and their hybrids is given in Section 5.

2.2. On the basis of morphology

Hollow microgel systems possess various morphologies and can be classified on the basis of variation in the shape of an internal cavity and outer polymeric network. The internal cavity may be spherical (Scotti et al. 2018) or elliptical (non-spherical) (Nickel et al. 2019), (Hao et al. 2004) and the outer polymeric network consists of either a single shell (Zhang and Wang 2008) or a double shell (Dubbert et al. 2015) as shown in Figure 1.

Figure 1:

Classification of hollow microgel systems on the basis of morphology. (a) Hollow microgels with a single shell and a spherical cavity, TEM image is reprinted from (Liu et al. 2013), copyrights (2013); with permission from Elsevier. (b) Hollow microgels with an elliptical core; TEM image reprinted from (Nickel et al. 2019), copyright (2019), with permission from American Chemical Society. (c) Multi-shell hollow microgels; TEM image is reprinted from (Brugnoni et al. 2018), copyright (2018), with permission from American Chemical Society.

2.2.1. Hollow microgels with single shell and a spherical cavity

Hollow microgels with a spherical cavity have been commonly described in literature (Dubbert et al. 2014; Liu et al. 2013; Nayak et al. 2005; Zhang and Wang 2008). They are synthesized by the dissolution of silica (SiO₂) core (Scotti et al. 2018), metal nanoparticle core (Contreras-Cáceres et al. 2015) and degradable polymeric core of a core–shell microgel system (Nayak et al. 2005). The size of cavity and the thickness of the shell of such kind of hollow microgel systems can be tuned by controlling core size, cross-linking density of shell, and external stimuli (Dubbert et al. 2014). Single-shell hollow microgels have been extensively documented in literature (Geisel et al. 2015; Scotti et al. 2018). Zhang and Wang (2008) have reported the fabrication of core shell microgel particles with poly(stryrene-co-N-isopropylacrylamide) (P[St-co-NIPAM]) core and poly(N--isopropylacrylamide) [PNIPAM] shell using seed mediated emulsion polymerization method. PNIPAM hollow microgel particles were achieved by dissolution of P(St-co-NIPAM) core by using tetrahydrofuran (THF) as etching agent. Resulting hollow microgel system was found temperature sensitive with volume phase transition temperature (VPTT) = 32 °C in aqueous medium. Zhang et al. (2005) have reported the production of hollow chitosan-based hydrogel microcapsules using layer by layer (LBL) strategy. Chitosan is a natural polysaccharide that bears a positive charge at low pH. Initially, chitosan and poly(acrylic acid) (PAA) was adsorbed on the pre-synthesized SiO₂ nanoparticles facilitated by acetate buffer (pH = 3.50). Gutaraldehyde was then introduced into the system to promote the cross-linking of chitosan. Later the system was treated with carbonate buffer (pH = 9.0) to induce pH control in the system and promote PAA mobility in the layers. This factor enhanced the removal of PAA from the layer assembly. The system now only contains cross-linked chitosan shell and SiO₂ core. The latter was removed by treating the system with hydrofluoric acid. This results in the manufacturing of hollow single component chitosan microcapsules that showed pH responsive phase transition at pH = 5.70, depending on the cross-linking density of the chitosan shell.

2.2.2. Hollow microgels with elliptical cavity

Hollow microgels with elliptical cavity may be considered more attractive in many applications because of their lower symmetries than the ones having spherical cavity. Hollow microgels with elliptical cavity have been reported in literature (Hao et al. 2004; Nickel et al. 2019). Nickel et al. (2019) have reported an anisotropic hollow microgel systems having tunable properties like softness and size, using an elliptical hematite core covered with a SiO₂ layer. Hematite was etched by hydrochloric acid (HCl) and SiO₂ core was etched using sodium hydroxide (NaOH). The same group (Nickel et al. 2022) has employed these hollow microgels to examine the effect of microgel architecture on self-assembly and interfacial deformation of anisotropic microgels. Hollow anisotropic microgels system act as promising system for studying combined effect of particle softness and shape anisotropy.

2.2.3. Multi-shell hollow microgels

Responsive multi-shell nano-gels (Schmid et al. 2016) and hollow double-shell microgels (Brugnoni et al. 2018; Dubbert et al. 2015; Li et al. 2010) have been discussed in the literature. Dubbert et al. (2015) have reported core–shell–shell hollow microgels with doubly temperature-sensitive behaviour. SiO₂ particles surrounded by cross-linked PNIPAM were used as seeds for construction of second shell of poly(N-isopropylmethacrylamide) [PNIPMAM]. The SiO₂ core of SiO₂@PNIPAM@PNIPMAM system was removed to obtain hollow microgels. The resulting hollow microgels have two values of VPTT at 32 °C and 43 °C due to the presence of two different thermo-sensitive PNIPAM and PNIPMAM shells, respectively.

2.3. On the basis of nature of functionalities of hollow microgels

Hollow microgel systems may consist of different organic and inorganic moieties in their network. So, on the basis of functionalities present in their network, hollow microgels may be classified as pure hollow microgels and hybrid hollow microgels. The microgels having no inorganic nanomaterial in their structures are called pure hollow microgels (Anakhov et al. 2022; Liu et al. 2013; Zhang et al. 2019) while hollow microgels having inorganic nanomaterials in their network are called hybrid hollow microgels (Lin et al. 2019). Following classification is based on functionalities of pure hollow microgels and nature of inorganic materials present in hollow microgels.

2.3.1. Functionalities of pure hollow microgels

Pure hollow microgels having sensitivity towards only one stimulus are called mono-responsive microgels and are usually obtained by polymerizing one monomer in the presence of some suitable cross-linker (Cheng et al. 2007; Wypysek et al. 2023). The hollow microgels having multi-responsive behaviour usually have more than one functionalities in their network. For example, hollow microgels made of NIPAM and some ionic moiety are called multi-responsive hollow microgels (Cheng et al. 2007; Lapeyre et al. 2009; Zhou et al. 2020). They show change in their size with change in any one of the stimuli (pH, temperature and ionic strength).

2.3.2. Inorganic nanoparticles loaded hollow microgels

Different inorganic nanoparticles can be loaded into hollow microgel system to obtain hybrid hollow microgels with characteristics of both organic and inorganic constituents. Different hollow microgel systems loaded with inorganic nanoparticles for various applications are described in Table 1. Hollow microgels loaded with zero-valent metal nanoparticles (Tripathi et al. 2014a; Xie et al. 2009) have been reported in literature. The presence of specific inorganic nanoparticles in a polymeric network gives specific properties to resulting hybrid microgel system which have been discussed in Section 5.2.

Table 1:

Different hybrids of hollow microgels based on the type of NPs loaded, their characterization and applications.

Sr. no.	System	NPs loaded	Characterization techniques	Applications	References
1	Poly(N-isopropylacrylamide)-silver [PNIPAM-Ag]	Ag	DLS, UV–vis scans, TGA, TEM	Catalytic	(Xie et al. 2009)
2	Gold-poly(N-isopropylacrylamide)-N-(3-aminopropyl)methacrylamide [Au-PNIPAM-APMA]	Au	AFM, UV–vis	Catalytic	(Tripathi et al. 2014a)
3	Gold-polydopamine [Au-PDA]	Au	SEM, TEM, UV–vis, FT-IR	Catalytic	(Lin et al. 2019)
4	Gold-poly(2-(1-methylimidazolium 3-yl)-ethyl methacrylate chloride)-poly [2-(dimethylamino)-ethyl methacrylate] [Au-PMIMC-PDMAEMA]	Au	TEM, TGA, FTIR, XPS, EDX, XRD,	Catalytic	(He et al. 2015)

3. Synthesis strategies used

Hollow microgels and hybrid microgels can be synthesized by different methods. Strategies to prepare, characterization, properties and applications of some of the hollow microgels and hybrid hollow microgels are described in Table 2. Generally hollow microgels are prepared from core–shell microgel systems. Some of the synthetic methodologies are described in detail as follow.

Table 2:

Preparation methods for different hollow microgels and their hybrids along with characterization, properties and application.

Sr. no.	System along abbreviation	Method of preparation	Characterization techniques	Properties	Application	References
1	N-isopropylacrylamide-N-(3-aminopropyl)meth-acrylamide-N, N′-methylene bis(acrylamide) [PNIPAM-APMA-BIS]	Surfactant based free radical polymerization	SEM, AFM, DLS	Hydrophilic	Catalytic, water purification, dye rejection	(Tripathi et al. 2014a)
2	Hollow poly (N-isopropylacrylamide)-silver [(PNIPAM)-Ag]	One-pot “self-removing” process followed by in situ reduction	TEM, DLS, UV–vis scan, TGA	Thermo-sensitivity	Catalytic	(Xie et al. 2009)
3	Poly(N-isopropylacrylamide)-poly (N-isopropylmethacrylamide) shell-shell [PNIPAM@PNIPMAM-SS]	Silica core dissolution	TEM, DLS, SLS	Thermo-sensitivity	Controlled uptake and release	(Dubbert et al. 2015)
4	Poly(N-isopropylacrylamide-co-itaconic acid) [P(NIPAM-co-IA)]	Silica core dissolution using NaOH and ester groups was saponified	SAXS, SANS, TEM, DLS	pH-sensitivity, ionic strength sensitivity	–	(Wypysek et al. 2020)
5	Hollow poly (N-isopropylacrylamide) [PNIPAM]	Synthesized by silica-core PNIPAM-shell microgels followed by core dissolution	SANS, DLS, MDS	Response in an overcrowded environment	Synthesis, separation, and catalytic	(Scotti et al. 2018)
6	Poly(N-isopropylacrylamide)-co-poly (acrylic acid) [PNIPAM-co-PAA]	Synthesized by semi-interpenetration polymer networks of PNIPAM-co-PAA/HPC followed by selective removal of HPC by pH change	FT-IR, DLS, TEM	pH-response and thermal response	Drug delivery	(Chen et al. 2012)
7	Hollow poly (N-isopropylacrylamide) microgels [PNIPAM]	Produced by seeded emulsion polymerization using P(St-co-NIPAM) particles as seeds	TEM, DLS, AFM, FT-IR	Temperature-sensitivity	–	(Zhang and Wang 2008)
8	Hollow poly(methacrylic acid) microgels [PMAA]	Layer by layer hydrogen bonded films of PMAA/poly-(N-vinylpyrrolidone)(PMAA/PVPON) were coated with manganese carbonate and core dissolution was done using hydrochloric acid	SEM, confocal microscopy	pH-sensitivity	–	(Kozlovskaya et al. 2011)
9	Hollow poly (N-isopropylacrylamide) microgels [PNIPAM]	Silica core-PNIPAM shell microgels were prepared by precipitation polymerization and silica core dissolution was made using NaOH.	SAXS, SANS	Temperature sensitivity	–	(Scotti et al. 2019)
10	Hollow poly (N-isopropylmethacrylamide) @ poly (N-isopropylacrylamide double shelled microgels [PNIPMAM@PNIPAM]	Silica core of PNIPMAM@PNIPAM shell microgels was dissolved using NaOH	DLS, cryo-TEM, SANS	Temperature sensitivity	–	(Brugnoni et al. 2018)
11	Hollow poly (N-isopropylacrylamide) microgels [PNIPAM]	Via microfluidic technique	SEM, FT-IR	Temperature sensitivity	Encapsulation of quantum dots and proteins	(Choi et al. 2008)
12	Hollow poly (N-isopropylacrylamide-co-ita-conic acid) microgels [P(NIPAM-co-IA)]	Silica core- P(NIPAM-co-IA) microgels were prepared by free radical precipitation polymerization followed by dissolution of core using NaOH	FLIM, UV–vis, DLS	pH-sensitivity	Encapsulation of cytochrome c	(Wypysek et al. 2023)

3.1. By dissolution of silica core

Core–shell hybrid microgels having hard SiO₂ in their core are prepared by polymerizing a suitable monomer in the presence of functionalized SiO₂ seeds. Then the dissolution of a SiO₂ core with the help of an etching agent (usually NaOH) is one of the most used methods for the preparation of hollow microgels as reported in the literature (Nickel et al. 2019; Schulte et al. 2018; Scotti et al. 2018). Dubbert et al. (2015) obtained a doubly temperature responsive hollow microgel system from a core–shell–shell microgel system. For this purpose, they initially synthesized a core–shell microgel system by multistep precipitation polymerization in the presence of SiO₂ particles. The pictorial view of synthesis of hollow microgel system with PNIPAM inner shell and PNIPMAM outer shell is given in Figure 2A. In the first step, NIPAM was polymerized in the presence of N,N ′-methylenebisacrylamide (BIS). This process was initiated by addition of potassium persulphate (KPS) into reaction mixture at 80 °C in aqueous medium. In the subsequent step, PNIPAM@SiO₂ particles were employed as seeds to carry out polymerization of N-isopropylmethacrylamide (NIPMAM) in the presence of BIS using KPS as initiator under same reaction conditions to produce PNIPMAM@PNIPAM@SiO₂ core–shell–shell microgels. SiO₂ core was removed by adding NaOH into the core–shell–shell dispersion as shown in Figure 2A. NaOH was also used to remove SiO₂ core from PNIPAM@SiO₂ core–shell microgel particles (TEM images shown in Figure 2B) to produce hollow PNIPAM capsules shown by TEM image in Figure 2C. TEM images for core–shell–shell were not provided. However, dynamic light scattering (DLS) data was used to confirm the fabrication of core–shell–shell and hollow shell–shell microgel systems. Liu et al. (2014) have synthesized thermoresponsive PNIPAM@SiO₂ core–shell microgels via seed mediated precipitation polymerization using SiO₂ nanoparticles as seeds, NIPAM as monomer, and BIS as cross-linker. Later the core was dissolved using hydrofluoric acid leaving hollow PNIPAM microgels. These pre-synthesized hollow microgels were fed in a liquid nitrogen bath, for unidirectional freezing. This induces arrangement in the hollow microgel particles leading to hollow microfibers.

Figure 2:

Synthesis of poly(N-isopropylmethacrylamide)@poly(N-isopropylacrylamide) doubly temperature sensitive core–shell–shell and hollow shell–shell microgel system including real TEM images. (Left) core–shell–shell, (right) hollow shell–shell microgels; adopted from (Dubbert et al. 2015), copyright (2014), with permission from Wiley-VCH.

Zha et al. (2002) have reported the fabrication of PNIPAM based hollow micro-containers from core–shell microgels system. For this purpose, monodispersed SiO₂ particles were prepared using Stöber method and were modified using 3-(trimethoxysilyl) propyl methacrylate (TMSPMA) which forms terminal C=C double bonds at the surface of core for enhanced interaction of inorganic substrate and organic moiety via covalent bond formation. Then to obtain core–shell microgel particles, the SiO₂ dispersion was used as seed during the precipitation polymerization of monomer PNIPAM. The polymerization process proceeded using BIS as cross-linker and KPS as initiator for 4 h at 70 °C to get core–shell microgels particles. SiO₂ cores were then etched using HF to obtain resultant hollow micro-containers.

3.2. By removal of polystyrene core

Synthesis of hollow microgel systems from a core–shell microgel system with polystyrene core and cross-linked polymeric shell via removal of core by calcination has also been reported in literature (Liu et al. 2013) as shown in Figure 3. Polyvinylpyrrolidone (PVP)-functionalized polystyrene (PS) particles were synthesized by emulsion polymerization in N₂ environment using 2,2′-Azobis(2-methylpropionamidine) dihydrochloride (AIBA) as initiator. In the next step, silica/PS hybrid particles (PS–SiO₂) were produced by Stöber process using tetraethyl orthosilicates (TEOS) as a source of SiO₂ in the presence of aqueous ammonia (NH₃ H₂O) and absolute ethanol. PS–SiO₂ particles were ultra-sonicated, washed with distilled water and dried in vacuum oven for 1 day at room temperature. Then PS core was removed by calcination at 500 °C to obtain hollow SiO₂ particles. Finally, thermo-sensitive hollow silica microgels (THSMGs) were fabricated by the polymerization of PNIPAM using BIS as cross-linker and KPS as initiator at 75 °C in the presence of PS-SiO₂ hollow particles already treated with 3-(trimethoxysilyl) propyl methacrylate (TMSPMA).

Figure 3:

Synthesis of thermo-responsive hollow SiO₂ microgels by PS core removal and its thermo-sensitive behaviour; adopted from (Liu et al. 2013), copyright (2013), with permission from Elsevier.

3.3. By the oxidation of gold core

Hollow microgel particles can also be obtained by removing metallic core of a core–shell microgel system with metallic core and cross-linked polymeric shell. Contreras-Cáceres et al. (2015) have reported synthesis of hollow microgel system from Au-PNIPAM core–shell microgels by dissolving Au-core via oxidation process. For this purpose, NIPAM was polymerized in the presence of Au colloidal dispersions under a nitrogen environment at 75 °C in aqueous medium. The reaction was allowed to continue for a few hours and then sonicated and filtered with distilled water. The gold core was oxidized with the help of cetyltrimethylammonium bromide (CTAB) and tetrachloroauric acid (HAuCl₄ 3H₂O) under mild stirring to obtain PNIPAM hollow microgel particles. The reaction was proceeded for about half an hour and then reaction mixture was centrifuged to remove excess CTAB and other byproducts of oxidation. The process of fabrication of PNIPAM hollow microgel particles from Au-PNIPAM core–shell microgels is shown in Figure 4. The number in Au64@PNIPAM and Au39@PNIPAM is the value of diameter of Au particles encapsulated in PNIPAM shell in nm.

Figure 4:

Fabrication of Au-PNIPAM core–shell microgels and gradual oxidation of Au core using HAuCl₄ and CTAB to form PNIPAM hollow microgels from Au@PNIPAM system; adopted from (Contreras-Cáceres et al. 2015), copyright (2014), with permission from American Chemical Society.

When HAuCl₄ is added to dispersion of Au@PNIPAM core–shell particles in the presence of CTAB, selective oxidation of Au-core in Au@PNIPAM microgels is occurred. The chemistry involved here is that on mixing, the CTA units bind with precursor salt i.e. HAuCl₄ which solubilizes in CTAB micelles. As HAuCl₄ is soluble in water so AuCl₄⁻ gets incorporated into micelles and forms ion pair with positive CTA head groups of CTAB micelles (Khan et al. 2013) (forming ion pair i.e. AuCl₄-CTA). The complexes (Au³⁺-CTA) can easily diffuse into the polymer gel network, the high porous structure of polymer network allows these complexes to diffuse and reach the Au nanoparticles present in core. Then redox reaction occurs between AuCl₄⁻ ions complexed with CTAB micelles (Rodríguez-Fernández et al. 2005) and Au nanoparticles (Au°) and in this way, Au³⁺ oxidizes Au nanoparticles in the presence of CTAB, as given in Scheme 1.

Scheme 1:

Formation of AuCl₄-CTA ion pair complex for carrying out oxidation of gold nanoparticles.

3.4. Etching of hematite and silica core

Nickel et al. (2019) have reported the synthesis of anisotropic hollow microgel system with tunable physical properties like size, shape and softness. They used silica coated elliptical hematite spindles (HSi) as core, which was reacted with TMSPMA to give reactive double bonds to SiO₂. NIPAM was polymerized on the surface of silica in the presence of BIS as cross-linker and KPS as initiator. Reaction was carried out at 65 °C and then at 80 °C. This led to the production of a hematite-silica-microgel (HSiM) core–shell system. The hematite and SiO₂ content of core was etched by using concentrated HCl and NaOH respectively as shown in Figure 5.

Figure 5:

Synthesis of hollow poly(N-isopropylacrylamide) polymeric network using elliptical hematite core coated with silica in the presence of N,N′-methylenebisacrylamide as cross-linker and potassium per sulfate as initiator; adopted from (Nickel et al. 2019), copyright (2019), with permission from American Chemical Society.

3.5. By oxidation of polymeric core

Nayak et al. (2005) have reported the synthesis of a core–shell microgel system with core made up of NIPAM cross-linked by N,N′-(1,2-dihydroxyethylene) bisacrylamide (DHEA) and shell made up of NIPAM cross-linked by BIS. Precipitation polymerization route was used for fabrication of both core and shell parts of the microgel system. Both polymerization steps were carried out at 70 °C in aqueous medium using APS as initiator under inert atmosphere. Finally, the core of core–shell microgel particles was degraded by adding aqueous solution of sodium periodate (NaIO₄) into the core–shell microgel dispersion at room temperature as shown in Figure 6. The cleavage of 1,2-glycol bond of DHEA by NaIO₄ resulted in conversion of cross-links into polymer segments which were removed by centrifugation. The percentage degradation of core can be controlled by controlling the ratio of NaIO₄/DHEA in core dissolution step. Resulting hollow microgel particles were found temperature responsive only. Multi-responsive hollow microgel systems can also been designed by using the same strategy. Fabrication of smart hollow microgels from core–shell microgels via oxidative removal of core and their usage as emulsifier has also been reported in literature (Vialetto et al. 2021). The detailed discussion on adsorption of such kind of hollow microgels at liquid interface is beyond the scope of this review. Zhang et al. (2007) have reported the synthesis of a glucose-responsive core–shell microgel system with a core made up of NIPAM cross-linked by DHEA and a shell made up of NIPAM and acrylic acid (AA) cross-linked by BIS and then modification was done to introduce phenyl boronic acid (PBA) groups in shell to make it glucose-responsive. At first, the fabrication of core and shell parts of the microgel system was done by carrying out polymerization at 70 °C in an aqueous medium using APS as an initiator under an inert atmosphere. Then DHEA-cross-linked PNIPAM core/BIS-cross-linked P(NIPAM-AA) shell microgels were modified by adding 3-aminophenylboronic acid (APBA) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (EDC) into core–shell microgel dispersion. The reaction mixture was kept at stirring at 0 °C for 2 h to fabricate core–shell microgel particles with DHEA-cross-linked PNIPAM core and BIS-cross-linked P(NIPAM-PBA) shell microgels. Finally, the core of core–shell microgel particles was degraded by adding an aqueous solution of NaIO₄ into the core–shell microgel dispersion to get a hollow P(NIPAM-PBA) glucose-responsive microgel particles.

Figure 6:

Synthesis of hollow poly(N-isopropylacrylamide) polymeric network by using a degradable core made of cross-linker N,N′-(1,2-dihydroxyethylene) bisacrylamide. The core is degraded after the addition of sodium periodate thus fabricating hollow PNIPAM microgel; adopted from (Nayak et al. 2005), copyright (2005), with permission from Wiley Online Library.

3.6. By self-removing process

Hollow microgel particles can also be obtained by “self-removing process”. Hollow PNIPAM particles have been prepared by this method (Xie et al. 2009). NIPAM was polymerized using KPS as initiator under N₂ environment at 70 °C without using any cross-linker to form PNIPAM. After completion of polymerization, cross-linker divinylbenzene (DVB) and NIPAM were added again into the reaction mixture. Reaction was run for 4 h at 70 °C and then left to cool down at room temperature for “self-removing” process. Non cross-linked PNIPAM globules were converted into coil conformation by decreasing the temperature of the reaction mixture. In this way, PNIPAM coil entrapped in central region was removed to get hollow PNIPAM microgel particles. Hollow PNIPAM microgel dispersion was loaded with Ag⁺ ions by addition of AgNO₃ solution. PNIPAM-Ag hybrid hollow microgels were synthesized by chemical reduction of AgNO₃ with KBH₄ in aqueous medium.

Core cannot be completely removed from core–shell microgel system using self-removing process by varying temperature to obtain perfectly hollow microgel system (Kwok et al. 2013; Vialetto et al. 2022; Virtanen et al. 2016).

3.7. Via self-assembly

One of the flexible and useful approaches to form materials for encapsulation is the self-assembly of particles at liquid-liquid interfaces (Dinsmore et al. 2002; Duan et al. 2005; Lin et al. 2003). Hollow microgels, particularly colloidosomes can be prepared by forming a layer of microscopic particles around liquid droplets. Lawrence et al. (2007) have described the formation of PNIPAM-co-AA anionic microgel particles stabilized droplets of the aqueous phase in 2-octanol and their locking to 2-octanol by adding diblock copolymer poly (butadiene-b-N-methyl 4-vinyl pyridinium iodide) by electrostatic interactions. For this purpose, first of all, they synthesized PNIPAM-co-AA microgel particles by the precipitation polymerization process using NIPAM and AA as monomers, SDS as surfactant BIS as cross-linker and potassium per sulfate (KPS) as initiator under N₂ purging. The reaction was carried out for 4 h at 70 °C under continuous nitrogen supply. The resultant microgels were dialyzed, centrifuged and re-dispersed in water. Then the hollow microgels or colloidosomes were prepared by using water droplets in oil as a template for assembling the PNIPAM-co-AA microgels particles. For this purpose, an aqueous suspension of PNIPAM-co-AA microgel particles was added to 2-octanol oil and the amphiphilic diblock copolymer poly(butadiene-b-N-methyl 4-vinyl pyridinium iodide) and gently shook for 10–15 min. This led to the formation of droplets and they were stabilized by the adsorption of PNIPAM-co-AA microgel particles to their surface. Then the solution was set aside for two days. Then after decantation, the solution was rinsed with ethanol to dissolve the template for the fabrication of hollow microgels. The pyridinium iodide block of the diblock copolymer is hydrophilic and cationic in nature. So, it was attached electrostatically to the anionic PNIPAM-co-AA particles. Due to which the PNIPAM-co-AA layers do not fell apart after the droplet interface was dissolved in ethanol, thus generating robust hollow microgels.

3.8. Microfluidic fabrication of hollow microgels

Microfluidic techniques are also applied for the synthesis of hollow microgels (Hu et al. 2015; Jans et al. 2019; Wang et al. 2014). Small consumption of reagents, rapid mixing of ingredients, and control over shape, size and size distribution are major advantages of microfluidic fabrication of hollow microgels over other conventional methods. Moreover, hollow microgel particles with diameter in range of 10–1000 μm can be obtained via microfluidic method that is not possible in case of fabrication of microgel particles obtained from core–shell microgel systems synthesized by multi-step conventional precipitation polymerization. The size of particles is usually less than 1 μm in case of fabrication of hollow microgels obtained from multi-step conventional emulsion polymerization. Guerzoni et al. (Guerzoni et al. 2017) manufactured polyethylene glycol microgel capsules using droplet microfluidics. The glass capillary microfluidic reactor with three inlets was used for this purpose. Water in oil in water (W/O/W) monodisperse double emulsions were obtained and used for hollow microgel fabrication. Six-armed star-shaped poly (ethylene oxide-stat-propylene oxide) (sPEG) was added in oil phase which act as cross-linker in UV light of 366 nm. The leads to the manufacture of size controlled microgel system. To study the loading and release of bioactive molecules the inner phase was replaced by fluorescein isothiocyanate–dextran (FTIC-dextran), that act as fluorescent biological proximity. The microgel capsule ability to retain and release FTIC-dextran was studied and it was found that microgel capsules synthesized by this route can retain molecules having size FTIC-dextran. Siltanen et al. (2017) have used coaxial flow microfluidic assembly for the successful manufacturing of hydrogel microcapsules that act as hollow capsules for cultivation of hepatocyte (Figure 7). The inner liquid of polyethylene glycol (PEG) and Optiprep densifier dissolved in Krebs–Ringer bicarbonate (KRB) buffer was used for core formation while 4-arm maleimide functionalized polyethylene glycol (PEG4MAL) was used for shell fabrication. The core–shell droplets were stabilized by organic continuous phase liquid (mineral oil) containing 0.5 % v/v span-80 surfactant. The cross-linker dithiothreitol (DTT) was added in a dropwise manner to promote shell formation.

Figure 7:

Cell encapsulation using the strategy of fabrication of hollow microgels via microfluidic flow focusing made of two aqueous streams containing polyethylene glycol (inner liquid) and 4-arm PEG-maleimide (PEG4MAL) (outer liquid) and two oil streams for emulsification and cross-linking; copyright (2017), with permission from Elsevier (Siltanen et al. 2017).

When hepatocytes had to be loaded, the core was mixed with freshly isolated hepatocytes and then was set to get emulsified in the system. Then oil/media system was allowed to sediment down in the aqueous phase. As the hepatocyte was mixed with the core during the polymerization so these hepatocyte-loaded hollow microcapsule systems showed more loading capacity. Because when cells are encapsulated in the microgels during the polymerization, they face no difficulty of diffusion while when cells are loaded in microgels after the completion of polymerization process, cells face difficulty in diffusion resulting in decreased loading capacity. Choi et al. (2008) manufactured thermo-responsive monodisperse PNIPAM microcapsules using a microfluidic strategy. This procedure uses single emulsion of water in oil (W/O) type. They used oil and water-based solutions. Hydrophilic solution (water) contained NIPAM as monomer and BIS as cross-linker while hydrophobic solution (oil) was n-hexadecane. 2,2-diethoxyacetophenone (DEAP) acted as photo initiator and injected perpendicularly to the continuous phase. Due to the irradiation of ultraviolet (UV) light, free radical polymerization was initiated at the interphase. Monomers were polymerized to form gel due to presence of DEAP in continuous phase. This method was capable of producing highly monodisperse PNIPAM microcapsules at room temperature which showed high thermal stability. The microcapsules were found to show small volume change bellow VPTT = 32 °C, but show drastic volume reduction above VPTT. But after 50 °C, no evident volume change was observed due to induced hydrophobicity by the isopropyl groups of PNIPAM. Zhang et al. (2009) have reported synthesis of poly(hydroxyethylmethacrylate-methylmethacrylate) (P[HEMA-MMA]) hollow microspheres using microfluidic technique. The aqueous solution containing APS, poly(vinyl pyrrolidone) (PVP) and glycerol and oil solution with ethylene glycol dimethacrylate (EGDMA), polyglycerol polyricinoleate (PGPR) and 1-octanol were separately pumped in microfluidic flow system which produced O/W emulsion. Nitrogen was passed through the emulsion to remove any oxygen followed by the irradiation of UV light which initiated polymerization and microspheres were produced, which were then treated with ethanol to get P(HEMA-MMA) hollow microspheres.

4. Characterization of hollow microgels and their hybrids

Different analytical tools and techniques are used to study the morphology, characteristics and properties of hollow microgels and their hybrids. These techniques includes, transmission electron microscopy (TEM) to study shape, size distribution and size of hollow microgels and their hybrids (Li et al. 2008a), X-ray photoelectron spectroscopy (XPS) to study the contents of different atoms present in hollow microgels (Li et al. 2008a), UV–vis spectroscopy (UV–vis) (Xie et al. 2009), scanning electron microscopy (SEM) to monitor the morphology of hollow microgels (Contreras-Cáceres et al. 2015), photon correlation spectroscopy to study the dependence of R_h of hollow microgels on temperature of the medium (Nayak et al. 2005), dynamic light scattering to predict R_h of hollow microgels (DLS) (Xie et al. 2009), field emission scanning electron microscopy (FESEM) (Liu et al. 2013), energy-dispersive X-ray spectroscopy (EDX) to study elemental mapping (Liu et al. 2013), small angle neutron scattering (SANS) to prove the presence of void above and below VPTT in hollow microgels (Scotti et al. 2018), fluorescence spectroscopy (Nayak et al. 2005), Fourier transmission-infrared spectroscopy (FT-IR) (Chen et al. 2012), static light scattering (SLS) (Nickel et al. 2019), atom force spectroscopy (AFS) (Lapeyre et al. 2009), cryo-TEM as a visualization method to study structural information of hollow microgels and their hybrids (Brugnoni et al. 2018), and small angle X-ray scattering (SAXS) (Wypysek et al. 2020). Contreras-Cáceres et al. (2015) studied stepwise dissolution of Au core of Au-P(NIPAM) core–shell microgel particles by Au oxidation to form hollow PNIPAM microgels by TEM. Figure 8 shows typical TEM images of Au@PNIPAM before (Figure 8A) and after 16 min (Figure 8B) of oxidation process where decrease in metal core dimension can be observed clearly. The decrease in diameter of central dark spots with time and ultimate their disappearance in TEM images was an indication of removal of core to form hollow microgels.

Figure 8:

Representative TEM images of the Au@PNIPAM particles (A) before and (B) after partial gold core oxidation; reproduced from (Contreras-Cáceres et al. 2015), copyright 2015, with permission from American Chemical Society.

They used DLS to confirm the low polydispersity in synthesized hollow microgel system. DLS has become an excellent tool in order to study the pH and temperature-responsive behaviour of hollow microgel particles in solution phase. Swelling, de-swelling and size distribution in hollow microgel systems can be accurately studied by DLS/PCS. To study the morphology of hollow microgels and their hybrids SEM, TEM and AFM are used (Tripathi et al. 2014a). To identify various functional groups present in microgels the widely used techniques are Raman spectroscopy (RS), FTIR, and nuclear magnetic resonance (NMR). Li et al. (2008b) used FTIR and XPS for the confirmation of fabrication of polymethacrylic acid shell around temperature-responsive hollow PNIPAM microspheres. UV/vis spectroscopy is used for the determination of VPTT of hollow microgels. It also helps in the confirmation of the formation of plasmonic metal nanoparticles inside microgel dispersion and to study their optical responsive behaviour. Metal contents in hollow microgels are determined by thermo-gravimetric analysis (TGA) (Xie et al. 2009). Wypysek et al. (Wypysek et al. 2020) have used SANS, SAXS and SLS to measure the changes in internal structure of poly(N-isopropylacrylamide)-co-poly(itaconic acid) hollow microgels in response to outer stimuli, i.e. pH, temperature and ionic strength. Using these techniques, they observed that the size of cavity increased due to the ionization of polymeric network and the cavity remained preserved above VPTT.

5. Properties of hollow microgels and hybrids

The properties of hollow microgels and their hybrids can be classified into two categories based on their structural constituents i.e. based on the polymeric network (hollow microgels) and inorganic material loaded into hollow microgels.

5.1. Based on the polymeric network

Some of the properties of hollow microgels and hollow hybrid microgels are produced due to functionalities present in the hollow polymeric network. These properties are described as follow.

5.1.1. Thermo-sensitivity

The microgel particles that exhibit a sudden change in their size when the temperature is changed are called thermo-responsive microgels. PNIPAM is the most used thermo-sensitive polymer microgel system (Pelton 2000). The PNIPAM microgel particles show sudden decline in their size at a particular temperature called VPTT which is 32 °C in aqueous medium. This swelling/de-swelling behaviour of the microgel system upon variation in temperature is called thermo-sensitivity of the microgel system. The decline in value of hydrodynamic radius (R_h) with rise in temperature is associated to conversion of hydrophilic polymeric network into hydrophobic network due to breakage of hydrogen bonding between amide group and water molecules. Temperature sensitive PNIPAM based hollow microgels have been widely reported in literature (Schmid et al. 2016; Scotti et al. 2018; Wypysek et al. 2020). Nayak et al. (2005) have reported thermo-responsive behaviour of hollow PNIPAM microgels in aqueous medium. Thermo-responsive behaviour of these hollow microgels was studied by measuring the hydrodynamic radius (R_h) of hollow microgel particles as function of temperature of the medium using photon correlation spectroscopy (PCS). The swelling ratio of hollow microgel system was compared with that of corresponding core–shell microgel system and found that hollow microgel system has better swelling ability than core–shell microgel system.

Contreras-Cáceres et al. (2015) have reported that thermo-responsive capabilities of hollow PNIPAM microgel system is affected by the mol percentage of BIS being used in the preparation of hollow PNIPAM microgels. The variation in the final morphology of hollow structure of PNIPAM particularly containing different BIS content was observed by cryo-TEM at two different values (25 °C and 50 °C) as shown in Figure 9A and C and Figure 9B and D. The mol percentage of BIS used during the synthesis of hollow PNIPAM microgels was varied from 5 to 17.5 mol %. For PNIPAM microgel system having 5 mol % BIS content, the volume of particles in their shrunken state was decreased by factor of 2 upon the removal of gold core at T ≥ VPTT (Figure 9E). But for PNIPAM microgel system with 10 mol % BIS content and 17.5 mol % BIS content, the volume of particles remains almost constant which indicates that at 10 % and 17.5 % BIS content, the polymeric network collapses at volume phase transition temperature (VPTT) without affecting the internal cavity. The cavity in hollow PNIPAM microgel particles in their collapsed state was observed only in case of microgel system with cross-linking density of 10 and 17.5 mol %. Hollow PNIPAM microgels at 5 mol % BIS content have low cross-linking density, so they show abrupt phase transition and cannot avoid total collapse thus, there is no residual cavity present (Figure 9A–B). Hollow PNIPAM microgels at 10 mol % BIS content and 17.5 mol % BIS content, respectively, have high cross-linking density with rigid structure, so owing to this rigidity the hollow PNIPAM microgel system is strong enough to avoid total shrinkage during collapse and thus the presence of hole was observed in their cryo-TEM images (Figure 9C–D). Doubly thermo-responsive core–shell–shell hollow microgels with inner shell made of PNIPAM) and outer shell made of PNIPMAM have been designed by Dubbert et al. (2015). Resulting PNIPAM@PNIPMAM microgel system showed volume phase transition (VPT) at two different values of temperature (32 °C and 42 °C). The hollow microgel network responds to variation in temperature of the medium in two steps as shown in Figure 10. Both shells are in swollen state below 32 °C (Figure 10C). The decrease in inner shell thickness was observed in the temperature range of 32 °C < T < 42 °C (Figure 10B) but no change in outer PNIPMAM shell was noted in this temperature range. Both inner and outer shells exist in shrunken state at T ≥ 42 °C (VPTT of PNIPMAM) (Figure 10A).

Figure 9:

Cryo-TEM imaging at different magnifications presenting hollow microgels containing 5.0 % and 10.0 % BIS below and above the VPTT. (A) 5.0 % BIS and 25.0 °C; (B) 5.0 % BIS and 50.0 °C: (C) 10.0 % BIS and 25.0 °C; and (D) 10.0 % BIS and 50.0 °C; (E) temperature dependence of the hydrodynamic diameter of Au@PNIPAM particles with 5.0 % (circle symbols), 10.0 % (square symbols) and 17.50 % (triangles) BIS cross-linking before and after (open and closed symbols, respectively) oxidation process, observed using DLS; reproduced from (Contreras-Cáceres et al. 2015), copyright (2015), with permission from American Chemical Society.

Figure 10:

Thermo-sensitivity of poly(N-isopropylmethacrylamide)@poly(N-isopropylacrylamide) shell-shell hollow microgel system; adopted from (Dubbert et al. 2015), copyright (2014), with permission from Wiley Online Library.

Vialetto et al. (2021) have described the thermo-responsive behaviour of hollow PNIPAM microgels using static light scattering (SLS) and DLS. They reported that when the temperature of the medium is at 40 °C, the value of D_h decreases from 520 nm to 490 nm. This decrease in D_h of PNIPAM based hollow microgels above VPTT clearly indicates that, upon removal of core, the outer shell (despite being thin ≃15 nm) does not buckle into the particle interior. The swelling ratio D_h (22 °C)/D_h (40 °C) of hollow microgel system (2.1 ± 0.05 nm) was compared with that of corresponding core–shell microgel system (1.66 ± 0.04 nm), this higher swelling ratio in case of hollow microgels was attributed to the fact that D_h (22 °C) increases with n (ratio of NaIO₄ to DHEA) and time.

5.1.2. pH-sensitivity

Hollow microgels may have some ionizable functionality like acidic and basic groups in their network. They respond to the change in pH (Chen et al. 2012; Li et al. 2008a). This property of hollow microgel system is called their pH sensitivity. Yang et al. (2009) have investigated pH responsive behaviour of poly(N,N′-methylenebisacrylamide-co-methacrylic acid) (P[BIS-co-MAA]) hollow polymeric microspheres using dynamic light scattering (DLS). At the pH = 2, the hollow P(BIS-co-MAA) microgel particles had a very large R_h value (>1000 nm) due to formation of large spherical particles as a result of aggregation of hollow polymeric microspheres. At pH = 7, hollow P(BIS-co-MAA) polymeric microspheres has R_h value in the range of 80 nm–96 nm depending upon the percentage of cross-linker in the feed composition. Further increase in pH from 7 to 12 leads to increase in R_h value from 105 nm to 114 nm due to electrostatic repulsion caused by ionization of carboxylic acid groups present in polymeric network. The pH-responsive change in R_h value of P(BIS-co-MAA) particles with different cross-linking degree shows the same trend.

Li et al. (2008a) have monitored the change in hydrodynamic diameter (D_h) of well-defined hollow microstructures made up of poly(methacrylic acid) (PMAA) network using DLS. The change in value of D_h of PMAA microspheres with change in pH of medium from pH = 4 to pH = 8 is shown in Figure 11A.

Figure 11:

(A) Plot of hydrodynamic diameter (D_h) of poly(methacrylic acid) (PMAA) hollow microspheres as a function of pH of the medium; adopted from (Li et al. 2008a), copyright 2008, with permission from American Chemical Society. (B) Effect of ionic strength on surface fuzziness of poly(N-isopropylacrylamide)-co-poly(itaconic acid) hollow microgels; adopted from (Wypysek et al. 2020), copyright 2019, with permission from Wiley Online Library.

The significant change in D_h value with change in pH of the medium was found around the pKa value of MAA. The increase in R_h value with increase in pH around pKa value of MAA is due to electrostatic repulsion between carboxylate groups of polymeric network.

5.1.3. Ionic-strength responsive behaviour

The change in size of hollow microgel particles with change in ionic strength of the medium is another important property of some hollow microgel systems and their hybrids. This property also arises due to presence of ionic functionalities of hollow polymeric network. Ionic-strength responsive micron sized hollow cross-linked polymeric systems have been widely reported in literature (Moncho-Jorda et al. 2019; Wypysek et al. 2020; Zhou et al. 2020). Wypysek et al. (2020) have reported the pH, temperature and ionic strength responsive behaviour of poly(N-isopropylacrylamide)-co-poly(itaconic acid) (P[NIPAM-co-IA]) copolymer hollow microgel particles in aqueous medium. They investigated the effect of ionic strength on fuzziness of hollow microgel particles by measuring Debye screening length under the medium of different ionic strength. The ionic strength (I) was adjusted as 0.1 mM, 1 mM, 10 mM and 50 mM changing the Debye length to 30 nm, 10 nm, 3 nm and 1 nm respectively. This variation in ionic strength can tune the fuzziness of external and internal surface of P(NIPAM-co-IA) network. It was reported that with increase in ionic strength from 0.1 mM to 50 mM at pH = 9, the external wall fuzziness decreases whereas fuzziness of cavity wall increases as shown in Figure 11B.

This decrease in external wall fuzziness and increase in fuzziness of cavity wall with increasing ionic concentration is attributed to non-uniform distribution of charges as well as addition of salt reduces electrostatic osmotic pressure. So, weak outward osmotic pressure is experienced by polymer chains near periphery of microgel particles due to which they are less stretched away from surface and hence the outer radius decreases. Similarly, polymer chains present near the inner wall of cavity also experiences weak outward pressure so these chains can now extend freely into cavity and are now less compressed against cavity wall thereby reducing the core radius as well. The shell thickness of P(NIPAM-co-IA) hollow microgels can be calculated by the difference between total inner radius and outer radius of these microgels, that difference arises by increased ionic strength and decreased electrostatic osmotic pressure. The shell thickness of P(NIPAM-co-IA) hollow microgels decreased from 191 nm to 147 nm when ionic strength was increased from 0.1 mM to 50 mM. Moreover, R_h also reduces from 380 nm to 220 nm with increase in ionic strength from 0.1 mM to 50 mM at pH = 9, this uniform reduction in R_h value is caused by screening of charges and the hydrophobic character imparted to the P(NIPAM-co-IA) hollow microgels by increased ionic strength.

5.1.4. Glucose responsiveness

The change in swelling degree and permeability of hollow microgel particles with change in glucose concentration of medium is also an important property of some hollow microgel systems. But this property is not as much widespread and generalized as compared to the other properties of hollow microgels like temperature response, ionic strength sensitivity and pH responsiveness. As for the presence of glucose responsive behaviour in hollow microgels, the presence of glucose responsive moiety like phenyl boronic acid in hollow polymeric network is must. Zhang et al. (2007) have reported hollow poly (N-isopropylacrylamide-phenyl boronic acid) P(NIPAM-PBA) system which shows rise in shell thickness with rise in glucose concentration in aqueous medium. As a result, the permeability of the shell can be enhanced by increasing the concentration of glucose in the medium. The concentration of glucose was varied as 0 M, 0.004 M, 0.01 M, 0.02 M and 0.05 M at pH = 8 to observe the effect of increase in glucose concentration on permeability of the P(NIPAM-PBA) shell.

The stabilization of charged form of phenylboronic acid (PBA) group by complexation with glucose as shown in Scheme 2 is the reason of swelling and permeability of the P(NIPAM-PBA) shell with an increase in glucose concentration of the medium. In addition to glucose sensitivity hollow P(NIPAM-PBA) particles are also temperature and pH responsive. The swelling and permeability of P(NIPAM-PBA) shell can be increase by increasing the glucose concentration and pH of the medium and decreasing the temperature of the medium. Table 3 gives various hollow microgel systems obtained from combination of various monomers along with their responsive properties.

Scheme 2:

Stabilization of charged form of phenyl boronic acid group (PBA) by complexation with glucose; adopted from (Zhang et al. 2007), copyright (2007), with permission from American Chemical Society.

Table 3:

Hollow microgel systems: characterization and properties.

Sr. no.	System	Characterization techniques	Features	References
1	Poly(N-isopropylacrylamide-co-itaconic acid) [P(NIPAM-co-IA)]	SAX, SANS, TEM, DLS	pH-sensitivity, ionic strength sensitivity, thermo-sensitivity	(Wypysek et al. 2020)
2	Poly(N-isopropylacrylamide)-co-poly(acrylic acid) [PNIPAM-co-PAA] hollow microgels	FT-IR, DLS, TEM	pH-sensitivity	(Chen et al. 2012)
3	Poly(N,N’-methylenebisacrylamide-co-methacrylic acid) [P(BIS-co-MAA)]	TEM, DLS, SLS	pH-sensitivity	(Yang et al. 2009)
4	Poly(N-isopropylmethacrylamide)@ poly(N-isopropylacrylamide) [PNIPMAM@PNIPAM] hollow microsphere	TEM, DLS, SLS	Doubly thermal responsive	(Dubbert et al. 2015)
5	Poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide) [PNB]	FT-IR, CLSM, SEM	Ion-sensitivity, thermo-sensitivity	(Wang et al. 2018)
6	Hollow cross-linked poly(N-isopropylacrylamide) microspheres [PNIPAM]	SEM	Thermo-sensitivity	(Sun and Deng 2005)

5.2. Based on nano material loaded

Loading of inorganic nanoparticles into hollow microgel system gives some additional properties to the resulting hollow hybrid microgels. For example, Xie et al. (2009) loaded silver nanoparticles (Ag NPs) to PNIPAM hollow microgel particles to produce hollow PNIPAM-Ag nanocomposite spheres. Ag NPs imparted special features to hollow microgels. Ag NPs slightly increases VPTT of PNIPAM microgel from 32 °C to 32.6 °C, due to cross-linking caused by donor–acceptor interaction between amide groups of PNIPAM microgels and loaded Ag NPs. As, Ag particles make the de-swelling of polymer network difficult, so higher temperature is required to cause VPT (Pich et al. 2004). PNIPAM-Ag nanocomposite spheres also possess optical properties due the presence of plasmonic NPs in network. Surface plasmon resonance wavelength (λ_SPR) is one of the most fascinating optical properties of the PNIPAM-Ag hybrid hollow microgel system which can be tuned by changing the temperature of the medium. For PNIPAM-Ag hybrid hollow microgel system, the value of λ_SPR was found 417 nm at 20 °C in aqueous medium and is shifted to higher wavelength with increase in temperature up to 50 °C due to change in refractive index around Ag NPs as result of VPT of the hybrid system. Optical temperature sensor can be developed on the basis of this change in λ_SPR with change in temperature.

6. Applications

6.1. Hollow microgels for fabrication and stabilization of metal nanoparticles

The hollow microgel particles can be used as micro-reactors for fabrication and stabilization of metal nanoparticles to get hybrid hollow microgels system. PNIPAM hollow microgel system has been reported as micro-reactor for the fabrication and stabilization of Ag NPs (Xie et al. 2009). For this purpose, Ag⁺ ions were loaded into cross-linked polymeric shell by addition of silver nitrate solution into aqueous dispersion of hollow PNIPAM microgels. Dialysis of Ag⁺ ions loaded microgel dispersion was performed before reduction of Ag⁺ ions to avoid the fabrication of Ag NPs in central cavity and outside the polymeric shell. Then Ag⁺ ions loaded into shell were reduced into Ag NPs using KBH₄ as reducing agent as shown in Figure 12. The number and size of Ag NPs loaded into hollow microgel system was found dependent of concentration of metal precursor used.

Figure 12:

Synthesis of poly(N-isopropylacrylamide-silver) hollow microspheres by the penetration of Ag⁺ ions of salt precursor followed by in-situ reduction with KBH₄; adopted from (Xie et al. 2009), copyright 2009, with permission from Wiley Online Library.

Tripathi et al. (2014a) synthesized gold nanoparticles (Au NPs) using ultra-thin membranes based on hollow microgels. The presence of large number of nitrogen in (poly [N-isopropylacrylamide]-N-[3-aminopropyl)methacrylamide) (PNIPAM-APMA) hollow microgels in the form of amides and amino groups helps to form coordinate covalent bond between nitrogen of amide groups of polymeric network and [AuCl₄]⁻ followed by the reduction to Au NPs by sodium borohydride (NaBH₄). Lin et al. (2019) have also reported the stabilization of Au NPs in polydopamine (PDA) hollow microcapsules. These Au NPs were firmly wrapped in cross-linked shell of PDA hollow microcapsules containing phenolic hydroxyl groups and amino groups, preventing Au NPs from being contaminated by solvent or from falling off.

6.2. Catalytic applications

Hollow microgels loaded with metal nanoparticles can be used as catalyst for various transformations. The open polymeric network and cavity filled with solution makes them potential support for catalytically active nanoparticles. The reactant molecules can easily diffuse into network to reach the catalyst surface because the hollow structure of microgel is conductive to enhance the mass transfer of reactants as it offers smaller diffuse resistance for mass transfer. Such features lead to enhanced catalytic activity of hollow hybrid microgels over traditional catalysts (Chen et al. 2016; Lin et al. 2013). Lin et al. (2019) have reported Au loaded on the surface of cross-linked PDA (Au-PDA) hollow microcapsules and studied their catalytic activity by reducing methylene blue (MB) dye in excess of NaBH₄. The catalytic activity of Au-PDA was monitored using UV–vis spectroscopy. When small amount of Au-PDA hybrid hollow microcapsules was added to the solution of MB dye in excess of NaBH₄, there was a sharp decrease in λ_max of MB dye from 664 nm within 10 min showing the catalytic progress of the Au-PDA catalyst. The color of MB dye solution also changed from dark blue to colorless indicating the occurrence of reaction. Externally tunable catalytic activity of smart hollow hybrid microgel system is another fascinating property of such kind of catalytic systems. The catalytic activity of PNIPAM-Ag hybrid hollow nano-spheres towards reduction of 4-nitrophenol (4-NP) into 4-aminophenol (4-AP) in the excess of KBH₄ in aqueous medium has been described in literature (Xie et al. 2009). Kinetics of the reaction was examined by UV–vis spectrometry. The decrease in value of absorbance at 400 nm (λ_max associated to 4-nitropheolate ions) with time and rise in absorbance at 300 nm (λ_max of 4-AP) with time was an indication of conversion of 4-NP into 4-AP on the surface of Ag NPs loaded into hollow microgel network. The value of apparent rate constant (k_app) was determined using pseudo first order kinetic model as given below.

$$-\frac{\text{d}{C}_t}{\text{dt}}=k_{\text{app}}{C}_t$$ (1)

Here C_t is concentration of 4-NP at any time, t is the time and k_app is apparent rate constant which was evaluated from the slope of ln $\frac{C_t}{C_o}$ versus time plot. The value of k_app for reduction of 4-NP with KBH₄ in the presence of PNIPAM-Ag in aqueous medium was evaluated at different values of temperature of the medium. The temperature dependence of k_app deviates from Arrhenius behaviour due to diffusional obstruction caused by VPT of PNIPAM-Ag hybrid microgels. Thermally tunable catalytic reduction of 4-NP into 4-AP by PNIPAM-Ag hybrid hollow microgels is shown in Figure 13 which depicts that reduction of 4-NP is fast at temperature less than VPTT of PNIPAM because hollow hybrid microgel system is in swollen state having hydrophilic character thus it becomes easier for 4-NP (being hydrophilic in nature) to reach towards catalytic surface but reduction of 4-NP becomes slow at temperature greater than or equal to VPTT of PNIPAM because hollow hybrid microgel system is in shrunken state with hydrophobic character which causes the diffusion of 4-NP towards catalytic surface difficult thus making reduction process of 4-NP slower.

Figure 13:

Thermally tunable catalytic reduction of 4-nitrophenol to 4-aminophenol with an excess KBH₄ using PNIPAM-Ag hollow microgels as catalyst.

Tripathi et al. (2014a) reported the ultra-thin thermo-responsive membranes based on hollow microgels for in-situ fabrication and stabilization of Au nanoparticles. The hybrid hollow microgels loaded on a porous membrane were used as catalysts for reduction of 4-NP into 4-AP with KBH₄ in aqueous medium as shown in Figure 14. The same microgel loaded with lactate dehydrogenase (LDH) based porous membrane was also used as biocatalytic system. This membrane based on hollow microgel system was proved as best substrate for holding and immobilizing LDH enzyme and its usage to catalyze the conversion of pyruvate to lactate as shown in Figure 14. This conversion of pyruvate into lactate was monitored indirectly using UV–vis spectrometry. The absorbance peak of nicotineamide dinucleotide (NADH) at 340 nm was found to decease with time gradually, indicating the conversion of pyruvate to lactate.

Figure 14:

Ultra-thin membranes-based hollow microgel system for catalytic and biocatalytic applications; adopted from (Tripathi et al. 2014a), copyright 2014, with permission from American Chemical Society.

The reaction for conversion of pyruvate to lactate in the presence of LDH enzyme is given in Scheme 3.

Scheme 3:

Reaction scheme for pyruvate to lactate conversion in the presence of lactate dehydrogenase (enzyme) loaded hollow microgel based membrane.

6.3. Drug loading and release

Hollow microgels usually possess a three-dimensional polymeric network which allows them to hold a large amount of water in their interstitial spaces (Haraguchi 2011; Xing et al. 2011a). This water holding capacity improves their biocompatibility with tissue cells and makes them feasible material having controlled drug-releasing properties. Owing to these mentioned features hollow microgels have been widely reported in literature for controlled drug delivery (Deloney et al. 2020; Hajebi et al. 2020; Heidari et al. 2022; Kazemi-Andalib et al. 2022; McMasters et al. 2017; Wang et al. 2022). Liu et al. (2013) reported that good cyto-compatibility of thermo-responsive hollow silica microgels (THSMGs) helps them to be used as efficient drug carrier. Rhodamine B (RHB) loaded in THSMGs show different release behaviour at different values of temperature. At 25 °C, the percentage release of RHB from THSMGs in 12 h is 82.5 % and at 45 °C, the percentage release of RHB from THSMGs in 12 h is 86.4 %. This temperature-controlled drug (RHB) release from THSMGs can be attributed to swelling and collapse of PNIPAM layers on surface of THSMGs. At 45 °C, more RHB release is because of the fact that PNIPAM is in shrunken state thus squeezing the RHB in shells of THSMGs thus opening the pores of hollow silica particles to enable RHB release from hollow core of THSMGs while at 25 °C, less RHB release is due to swollen state of PNIPAM layers on surface of THSMGs. Lee et al. (2007) reported that hollow polyelectrolyte microcapsules composed of HA/PLL (hyaluronic acid/poly-L-lysine hydrobromide) demonstrate pH responsive permeability due to which this system is used for pH--controlled drug release of fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (BSA). FTIC-BSA released faster from microcapsules at pH = 5 than at pH = 7, due to swelling of the hollow microcapsule and increasing permeability of microcapsule walls.

6.4. Facile detection of trace Pb²⁺

Lead (II) is one of the most toxic and abundant heavy metal ions (Liu et al. 2017). It may cause a wide range of problems to humans if ingested or accumulated. Major health issues include mortality, neurological issues, adverse pregnancy outcomes and many more (Landrigan et al. 2002). Microgel based detection of heavy metal ions like lead (II) has become the matter of concern (Lin et al. 2016) but here in only use of hollow microgels for this purpose has been described. Wang et al. (2018) has reported a simple device equipped with non-woven fabric filter medium immobilized on ion-detectible hollow microgels for facile recognition of Pb²⁺ in aqueous environment. The device is based on poly(N–isopropylacrylamide-co-benzo-18-crown-6-acrylamide) (PNB), in which NIPAM groups act as actuator and 18-crown-6 groups act as the sensors for Pb²⁺. With the passage of solution of Pb²⁺ through non-woven fabric filter medium, the Pb²⁺ ions are captured by18-crown-6 groups thus forming stable 18-crown-6/Pb²⁺ complexes. This causes electrostatic repulsion between charged 18-crown-6/Pb²⁺ complex groups and as a result of which hydrophilicity of PNB hollow microgels increases. Thus, PNB hollow microgels changes isothermally from shrunken state to swollen state by tracing Pb²⁺. So, PNB hollow microgels loaded on non-woven fabric filter material converts concentration of Pb²⁺ solution into the change of flux of solution passing through the filter medium, behaving as Pb²⁺ responsive microvalves.

7. Conclusion and future directions

Hollow microgels and their hybrids have gained much attention due to their fast and excellent responsive behaviour towards external stimuli in comparison to other conventional microgel systems. Hollow microgels are the best known for their uptake and release properties. The presence of a cavity in the central region of the microgel particles makes them soft material with excellent and quick response towards external stimuli. They are being used in the field of drug delivery, water purification, sensors, optical devices, catalysis and many more. This review briefly describes the peculiar properties of hollow microgels, their response to different environmental stimuli and their applications in various fields.

Hollow microgel particles are usually obtained from core–shell microgel particles by dissolution of central core by using suitable reagent called etching agent under optimized conditions. This report is a quick review of recent research progress in the field of hollow microgels and may be helpful for new researchers who are keen to do more work in this area. New methods for the fabrication of hollow microgels with required properties may be developed in future work. Most of the work reported on thermo-responsive hollow microgels is based on NIPAM. Other thermo-responsive hollow microgel systems may be developed by using monomer other than NIPAM e.g., vinylcaprolectam. A limited number of reports are available on fabrication of silver (Xie et al. 2009) and gold (Tripathi et al. 2014a) nanoparticles within hollow polymeric network. Fabrication and stabilization of nanoparticles of other metals like Pd, Pt and Rh may be carried out in future studies. Catalytic activity of Pd, Pt and Rh nanoparticles loaded into hollow microgel system may be investigated. Various organic transformations may be carried out in the presence of Pd, Pt and Rh nanoparticles loaded into hollow microgels to get fine chemicals. Detailed investigation of optical characteristics of plasmonic nanoparticles loaded in hollow microgels may be a subject of interest in future. Photo-responsive drug delivery systems may be developed by loading gold nanorods in hollow microgel systems.

Abbreviations

4-AP

4-Aminophenol

4-NP

4-Nitrophenol

AA

acrylic acid

AFS

atom force spectroscopy

Ag NPs

silver nanoparticles

Ag

silver

AgNO₃

silver nitrate

AIBA

2,2′-Azobis(2-methylpropionamidene) dihydrochloride

APBA

3-Aminophenylboronic acid

APMA

N-(3-Aminopropyl)methacrylamide

APS

ammonium persulphate

Au NPs

gold nanoparticles

Au

gold

BIS

N,N′-methylenebisacrylamide

BSA

bovine serum albumin

CTA

cetyltrimethylammonium

CTAB

cetyltrimethylammonium bromide

DEAP

2, 2-diethoxyacetophenone

D_h

hydrodynamic diameter

DHEA

N,N’-(1,2-dihydroxyethylene) bisacrylamide

DLS

dynamic light scattering

DTT

dithiothrietol

DVB

divinylbenzene

EDC

N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride

EDX

energy-dispersive X-ray spectroscopy

EGDMA

ethylene glycol dimethacrylate

FESEM

field emission scanning electron microscopy

FITC

fluorescein isothiocyanate

FT-IR

fourier transmission-infrared spectroscopy

HA

hyaluronic acid

HAuCl₄.3H₂O

tetrachloroauric acid

HCl

hydrochloric acid

HEMA

hydroxyethylmethacrylate

HF

hydrofluoric acid

HsiM

hematite-silica microgel

HSPs

hollow silica particles

IA

itaconic acid

KBH₄

potassium borohydride

KPS

potassium persulphate

LBL

layer by layer

LDH

lactate dehydrogenase

MAA

methacrylic acid

MMA

methylmethacrylate

N₂

nitrogen

NaBH₄

sodium borohydride

NADH

nicotineamide dinucleotide

NaIO₄

sodium periodate

NaOH

sodium hydroxide

NIPAM

N-isopropylacrylamide

NMR

nuclear magnetic resonance

NPs

nanoparticles

PAA

poly-acrylic acid

Pb⁺²

lead ions

PBA

phenylboronic acid

PCS

photon correlation spectroscopy

Pd

palladium

PDMS

polydimethylsiloxane

PEG

polyethylene glycol

PGPR

polyglycerol polyricinoleate

PLL

poly-L-lysine hydrobromide

PMAA

poly(methacrylic acid)

PNB

poly(N-isopropylacrylamide-co-benzo-18-crown-6-acrylamide)

PNIPAM

poly(N-isopropylacrylamide)

PNIPMAM

poly(N-isopropylmethacrylamide)

PS

polystyrene

Pt

platinum

PVP

polyvinylpyrrolidone

R_h

hydrodynamic radius

RHB

rhodamine B

RS

Raman spectroscopy

SANS

small angle neutron scattering spectroscopy

SEM

scanning electron microscopy

SiO₂

silica

SLS

static light scattering

TEM

transmission electron microscopy

TGA

Thermogravimetric analysis

THF

tetrahydrofuran

THSMGs

thermo-responsive hollow microgels

TMSPMA

3-(trimethoxysilyl) propyl methacrylate

UV

ultraviolet

UV–vis

UV–visible spectroscopy

VPT

volume phase transition

VPTT

volume phase transition temperature

XPS

X-ray photoelectron spectroscopy

Biographies

Ahmad Hassan

School of Chemistry, University of the Punjab, New Campus, Lahore 54590, Pakistan

Ahmad Hassan is presently enrolled in M.Phil. Chemistry at School of Chemistry, University of the Punjab (PU), Lahore, Pakistan, under the supervision of Dr. Farooqi. He obtained his BS degree in Chemistry from the same institute in 2021. His area of research is polymer stabilized metal nanoparticles for catalysis.

Iqra Sajid

School of Chemistry, University of the Punjab, New Campus, Lahore 54590, Pakistan

Iqra Sajid is presently enrolled in M.Phil. Chemistry at School of Chemistry, University of the Punjab (PU), Lahore, Pakistan, under the supervision of Dr. Farooqi. She obtained her BS degree in Chemistry from the same institute in 2021. She completed her BS dissertation under the supervision of Dr. Farooqi. Her area of research is polymer microgels and their hybrids for environmental and catalytic applications.

Shuiqin Zhou

Department of Chemistry of College of Staten Island and Ph.D. Program in Chemistry, The City University of New York, 2800 Victory Boulevard, Staten Island, NY 10314, USA

Shuiqin Zhou received her BS (1988) and MS (1991) from Xiamen University, China, and her PhD (1996) from The Chinese University of Hong Kong. She received postdoctoral training at SUNY at Stony Brook and then worked at Union Carbide/The Dow Chemical Company as a senior chemist. She started her own research lab at The City University of New York at CSI in 2002 and is currently a professor of Chemistry at Department of Chemistry of College of Staten Island and Ph.D. Program in Chemistry, The City University of New York, 2800 Victory Boulevard, Staten Island, NY 10314, USA, working in field of gel-based nanomaterials for biosensing and smart drug delivery.

Robina Begum

School of Chemistry, University of the Punjab, New Campus, Lahore 54590, Pakistan robina.hons@pu.edu.pk https://orcid.org/0000-0002-0470-3374

Robina Begum is an assistant professor at School of Chemistry, University of the Punjab, Lahore. She obtained her PhD degree in Chemistry from the same institute in 2019. She carried out a part of her research work in the laboratory of Prof. Jianliang Xiao at Department of Chemistry, University of Liverpool, UK as a split-site PhD scholar funded by Commonwealth Scholarship Commission, UK. Her research area is organic–inorganic hybrid materials for various applications.

Zahoor H. Farooqi

School of Chemistry, University of the Punjab, New Campus, Lahore 54590, Pakistan zhfarooqi@gmail.com https://orcid.org/0000-0003-3200-2935

Zahoor H. Farooqi is an associate professor at School of Chemistry, University of the Punjab, Lahore, Pakistan. He worked as a research associate in CSI, CUNY, New York, USA, from January 2009 to March 2010. In 2018, Dr. Farooqi worked for five months as a honorary research fellow in Department of Chemistry, University of Liverpool, UK, and from November 2022 to January 2023 as a visiting academic staff member in Department of Chemical Engineering, Loughborough University, UK. His area of research is microgels loaded with inorganic nanoparticles for catalytic applications.