Four-Dimensional Bioprinting for Regenerative Medicine: Mechanisms to Induce Shape Variation and Potential Applications

Abstract

Regenerative medicine is an exciting field of research, in which significant steps are being taken that are leading to the translation of the technique into clinical practice. In the near future, it is expected that clinicians will have the opportunity to bioprint tissues and organs that closely mimic native human tissues. To do so, imaging of patients must be translated to digital models and then fabricated in a layer-by-layer fashion. The main aim of this review is to elaborate on the possible mechanisms that support four-dimensional bioprinting, as well as provide examples of current and future applications of the technology. This technology, considering time as the fourth dimension, emerged with the aim to develop bioactive functional constructs with programmed stimuli responses. The main idea is to have three-dimensional-printed constructs that are responsive to preplanned stimuli. With this review, the authors aim to provoke creative thinking, highlighting several issues that need to be addressed when reproducing such a complex network as the human body. The authors envision that there are some key features that need to be studied in the near future: printed constructs should be able to respond to different types of stimuli in a timely manner, bioreactors must be developed combining different types of automated stimuli and aiming to replicate the in vivo ecology, and adequate testing procedures must be developed to obtain a proper assessment of the constructs. The effective development of a printed construct that supports tissue maturation according to the anticipated stimuli will significantly advance this promising approach to regenerative medicine.

Four-Dimensional (Bio-)printing: A Review on Stimuli-Responsive Mechanisms and Their Biomedical Suitability

“…However, some reviews on stimuli-responsive materials have already been provided in other fields [5,26,41], it is now highly relevant to clarify their suitability for biomedical applications. Indeed, the functionality changes of a 4D bioconstruct critically depend on the given stimulus and material choice that are selected based on the desired application [42]. Polymers able to react to stimuli undergo changes in their properties, like size or shape, as well as permeability, mechanical, surface, optical, and electrical properties after applications of physical stimuli, such as temperature, light, electric, mechanic, and magnetic fields, and they will be described in the next sections.…”

In situ Enabling Approaches for Tissue Regeneration: Current Challenges and New Developments

“…More recently, and due to its potential in the biomedical field, 3D bioprinting arose, which enables the production of complex structures with biological components (Mandrycky et al, 2016). However, one major limitation remains, since only the initial state of the printed structure is considered, and the influence of time and stimuli is ignored (Gao et al, 2016;Momeni et al, 2017;Morouço and Gil, 2019). Thus, 4D has been presented as the next generation of tissue regeneration and intends to mimic not only the organs' or tissues' architecture and properties, but also their dynamic function (Gao et al, 2016;Momeni et al, 2017).…”