Recently materials with unique properties that probably alter their properties with the response to their outer environment have been of great interest. These polymers and hydrogel materials were called environmental, responsive, stimuli-responsive, and smart [
1‐
6]. There are several kinds of responsiveness, e.g., temperature, pH, light, ionic strength, and shape [
7‐
11]. A dual response has been prepared by combining two or more monomers or polymers with different stimuli-responsiveness [
12‐
15].
N-isopropylacrylamide (NIPA) has considered the most familiar thermo-responsive monomer and was used for the preparation of many thermo-responsive polymers and hydrogels; it exhibits phase separation (lower critical solution temperature LCST) with increase in the temperature to 32 ℃ [
16,
17]. 3D polymer network is called gel or hydrogel (aqua-gel) in the case of hydrophilic polymers capable of absorbing a large amount of water [
18‐
20]. The importance of gel technology has been widely spread due to highly successful industrial applications, e.g., cell culture, self-healing, and drug delivery [
21‐
26]. Thermo-responsive hydrogel based on
N-isopropylacrylamide has been attended by many scientists [
27,
28]. Several articles have focused on preparing thermo-responsive micro/nanogel and studied the swelling properties in water by heating and cooling as a reversible process [
29,
30]. The importance of glycerol in the industrial field has increased [
29]; it was used to modify several organic compounds; one of the most important modifications is the formation of sol-ketal [
32]. The sol-ketal monomer is one of the keys to getting polymers and hydrogel with a reactive hydroxyl group [
33,
34]. The hydrolysis of sol-ketal acrylate was used to produce a new monomer known as glycerol monomethacrylate [
35]; it was used as a new monomer in the formation of biocompatible [
36]. The presences of hydroxyl groups in glycerol monomethacrylate encourage material scientist to use it instead of (2-hydroxyethyl methacrylate-HEMA) in the fabrication of contact lenses [
37]. In the last few decades, many reactions and polymerization have been improved to sol-ketal acrylate, e.g., atom transfer radical polymerization (ATRP) and grafting [
38‐
41]. Introducing hydrophobic monomers into the thermo-responsive polymers or gel will affect the lower critical solution temperature toward lower values [
13]. Vanillin is interested in preparing functional monomers for the reactivity of its functional groups [
42,
43]. Their derivatives can be easily separated and collected. A recent article has prepared a vanillin derivative and used it to synthesize bio-based polymer [
44‐
46]. A functional gel is a gel that contains at least one functional group and can make chemical modifications; it has been implemented in several routes, like click chemistry [
47]. The reactivity of the functional group was used in the formation of binding with several biomolecules applicable in the biosensor and chromatographic methods [
48].
Moreover, the advanced medication used the attachment and release of biomolecules in polymer drug delivery [
49]. The hydrogel films with the functional group and stimuli-responsive layer have been recently studied; the swelling properties were measured using surface plasmon resonance spectroscopy with optical waveguide spectroscopy (SPR/OW) [
2,
50‐
52]. The (SPR/OW) technology has been implemented to investigate the change in the LCST (
Tc) of the swollen hydrogel in water and different pH solution as a function of the refractive index or volume degree of swelling with temperature variation [
42,
53,
54]. Many articles were published and discussed the applications of responsive hydrogel in biological and medical technology, e.g., the sensor (biosensor) [
52,
55], biotechnology [
56], and switchable wettability [
46]. This work focused on fabricating a functional hydrogel bilayer by assembly layer-by-layer with hydrophilic/hydrophobic chains; such hydrogel can be used as a biological vessel to attach and release biomolecules.