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Review
. 2025 Mar 7;26(1):2475736.
doi: 10.1080/14686996.2025.2475736. eCollection 2025.

Molecular design of dynamically thermoresponsive biomaterials

Jun Kobayashi  1 , Masamichi Nakayama  1 , Kenichi Nagase  2
Affiliations
Review

Molecular design of dynamically thermoresponsive biomaterials

Jun Kobayashi et al. Sci Technol Adv Mater. .

Abstract

Dynamically thermoresponsive biomaterials, particularly those utilizing poly(N-isopropylacrylamide) (PNIPAAm), have attracted much attention in biomedical applications due to their reversible phase transition near body temperature. These biomaterials provide innovations across drug delivery system, chromatography, and tissue engineering. Molecular designs, such as the incorporation of hydrophilic comonomers or graft copolymers in PNIPAAm hydrogels, enhance rapid kinetics of the gels when jumping the temperature across the phase transition temperature, because of avoiding 'skin layer' formation on the surface of the gels. Nanocarriers possessing PNIPAAm coronas facilitate spatial drug delivery and temporally on-demand drug release to targeted cancers in combination with hyperthermic therapy. Downsizing of PNIPAAm hydrogels accelerates the kinetics of shrinkage/swelling, leading to applications as thermoresponsive chromatographic matrices and cell cultureware. PNIPAAm-modified surfaces support thermoresponsive cell culture systems for the non-invasive recovery of intact cell sheets, enabling advanced regenerative therapies and layered 3D tissue formation. Recent developments also integrate growth factor delivery for sustained cell stimulation on culturewares. Newly developed biomaterials, including dynamically thermoresponsive PNIPAAm, are expected to expand the opportunity for novel treatment technologies such as targeted therapies and regenerative medicine.

Keywords: Thermoresponsive polymer; bioseparation; chromatography; drug delivery system; poly(N-isopropylacrylamide); tissue engineering, cell sheet, regenerative medicine.

Plain language summary

This paper focuses on epoch-making dynamically thermoresponsive biomaterials through designing molecular architectures, such as polymer grafting structures, monomer design, and the size effects of molecules.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Scheme of molecular design of thermoresponsive poly(N-isopropylacrylamide) (PNIPAAm) for biomedical applications.
Figure 2.
Figure 2.
Schematic illustration of deswelling process for (a) Normal-type PNIPAAm gel and (b) Its graft-type or hydrophilic copolymer-type gel.
Figure 3.
Figure 3.
Schematic illustration of thermoresponsive nanocarriers with PNIPAAm segments. (a) PNIPAAm-modified liposome and (b) PNIPAAm-based block copolymer micelles.
Figure 4.
Figure 4.
Schematic illustration of thermoresponsive chromatography. (a) Concept of thermoresponsive chromatography and (b) Chromatograms at 10°C and 50°C.
Figure 5.
Figure 5.
Schematic illustration of thermoresponsive cell separation materials. (a) Thermoresponsive cationic copolymer brush, (b) thermoresponsive polymer brush with affinity peptide, (c) thermoresponsive microfiber, and (d) thermoresponsive cell separation column.
Figure 6.
Figure 6.
Cell sheet preparation using a temperature-responsive cell culture surface. PNIPAAm-grafted surface exhibits hydrophobicity and is cell adhesive at 37°C, and changes to hydrophilic and cell non-adhesive at 20°C. The PNIPAAm-grafted surface enables the cultured cells to detach themselves as a contiguous sheet only upon reducing temperature. The detached cell sheet holds ECM beneath the sheet. Reprinted from Kobayashi, J. (2019) [10] with permission from Wiley.
See this image and copyright information in PMC

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