Injectable Hydrogels for 3D Bioprinting

Insup Noh, Xiumei Wang, Sandra van Vlierberghe, Insup Noh, Xiumei Wang, Sandra van Vlierberghe

• Publisher: Royal Society of Chemistry
• Year: 2021
• eBook ISBN: 9781839163982
• Edition: 1
• Topic: Technology & Engineering
• Subtopic: Biomedical Science
• Index: Technology & Engineering

Hydrogels represent one of the cornerstones in tissue engineering and regenerative medicine, due to their biocompatibility and physiologically relevant properties. These inherent characteristics mean that they can be widely exploited as bioinks in 3D bioprinting for tissue engineering applications as well as injectable gels for cell therapy and drug delivery purposes. The research in these fields is booming and this book provides the reader with a terrific introduction to the burgeoning field of injectable hydrogel design, bioprinting and tissue engineering.

Edited by three leaders in the field, users of this book will learn about different classes of hydrogels, properties and synthesis strategies to produce bioinks. A section devoted to the key processing and design challenges at the hydrogel/3D bioprinting/tissue interface is also covered. The final section of the book closes with pertinent clinical applications.

Tightly edited, the reader will find this book to be a coherent resource to learn from. It will appeal to those working across biomaterials science, chemical and biomedical engineering, tissue engineering and regenerative medicine.

Chapter 1

Overview of Injectable Hydrogels for 3D Bioprinting and Tissue Regeneration

Gopinathan Janarthanan^a,b and Insup Noh^a,b

^a Department of Chemical and Biomolecular Engineering, Seoul National University of Science and Technology Seoul 01811 Republic of Korea

^b Convergence Institute of Biomedical Engineering and Biomaterials, Seoul National University of Science and Technology Seoul 01811 Republic of Korea Email: [email protected]

1.1 General Introduction

One of the major clinical issues related to accidental injuries among the aging population is the development of soft and hard tissue defects or damages.^1,2 Clinically, the patients are treated with surgical reconstruction, organ transplantation, artificial implants, etc.³ Even though allograft or autograft transplantation is the most commonly used method, donor shortage and donor morbidity are still very important issues.⁴ Owing to such limitations, the number of patients waiting for transplants grows annually, and they require alternative treatment methods to avoid such a long wait.^5,6 Recently, 3D bioprinting has received noticeable attention, and it has progressed vastly with the advancing technologies and materials.^7,8 Generally, the diseased or damaged tissue or organ is identified and further scanned using magnetic resonance imaging (MRI) or micro-computerized tomography (μ-CT) scans. Then, the images are reconstructed using specific software to obtain the 3D models. Further, these 3D models are converted to G-codes using a slicing software. These G-codes are then uploaded into 3D printers and printed on demand using biocompatible materials or the patients’ cells isolated from bone marrow, adipose tissue or other sources that can be used in the bioinks, which consist of hydrogels encapsulating both the stem cells and the bioactive molecules.^9,10 3D bioprinting by additive manufacturing is one of the most modern, promising technologies for scientists to develop complex tissues and organ constructs.^11–13 With these modern biofabrication techniques, the researchers can create tissue structures similar to the native tissues or organs with biomimetic functionalities. The 3D bioprinting process generally involves the deposition or addition of live cell added hydrogel (bioinks) biomaterials in well-arranged layers to obtain a 3D construct, which is capable of creating functional tissues or organs.^11,12 The desired 3D design and structural pattern are generally developed using computer-aided design (CAD) models. The whole 3D bioprinting process requires novel polymeric biomaterials, design software, coding software, movement controllers in 3D or 4D axis, sterile environment, etc., apart from the live cells that are the primary constituent of the bioink.⁹ This method enables us to create more intricate structures with high precision and control as well as homogeneous cell distribution, which are normally not possible in the other scaffold preparation methods reported previously. This technique has many advantages such as high precision, well-ordered pore structures, vast and complicated designs, fast process and even patient-specific customization with less time.^13–15 This helps in personalized medicine as well, where the individual's organ or damaged tissue can be scanned using MRI or μ-CT scans, and subsequent images can be ordered and processed in specific software to obtain 3D models. Further, these 3D models can be processed on demand and used to print economically viable patient-specific 3D constructs with high precision and customization within a short time period.^16–18

Even though there are several 3D printing techniques reported in the literature, only a handful of techniques is routinely used in 3D bioprinting or biofabrication for tissue engineering and regenerative medicine as well as drug screening. These are mainly pneumatic or screw-based extrusion printing techniques such as direct ink writing (DIW), laser-induced forward transfer, inkjet bioprinting, stereolithography (SLA) and finally selective laser sintering (SLS).^11,19 In DIW, the bioinks containing cells and hydrogels are extruded from a nozzle to create the desired 3D structures using the preloaded 3D models. However, in inkjet printing, at high shear rates, the low-viscosity bioinks are deposited or added as droplets. The other methods mentioned earlier require light-curable or laser-reactive groups in the biomaterial to make the 3D structures. Also, they need sophisticated instruments for the printing process. Apart from these methods, several techniques such as electro-hydrodynamic printing, microwave- and acoustic-based bioprinting have been reported recently for 3D bioprinting.^11,13,20

For all the 3D bioprinting techniques, the primary component is the bioink containing cells in normal hydrogels to produce engineered/artificial live tissues. The bioinks are the heart of the 3D bioprinting; hence, the selection of the bioink is highly critical to obtain the desired results. In bioink preparation, the hydrogels play a dominant role by enveloping cells for the protection of cells during bioprinting.^12,21,22 The hydrogels mimic the biological and physico-chemical properties of the native tissues and provide the necessary environment for cells to live, grow and proliferate, leading to tissue regeneration.^23–26 They offer a convenient environment by providing proper nutrient transport, waste removal, oxygen–carbon dioxide exchange and cell attachment site. The hydrogels can be easily modified through chemical modifications, and their rheological, degradable or mechanical properties can be altered.²⁷ Apart from these reasons, these hydrogels exhibit shear thinning properties even while accommodating the live cells, without significantly affecting them.²⁸ Therefore, it becomes one of the ideal candidates for bioink preparations that can be used in 3D bioprinting.^29,30 This book provides more in-depth information about hydrogels, their various forms and synthesis methods, the characterization of different properties that can be applied in 3D bioprinting for tissue regeneration and clinical applications and the issues with intellectual properties and US-Food and Drug Administration (FDA) approval.

The emergence of 3D printing hydrogels and their importance can be evidently observed from the surge of research publications in recent years as shown in Figure 1.1d. “Hydrogel”, “injectable gel”, “injectable hydrogels” and “3D print hydrogels” were used as the search keywords in the PubMed website, and the subsequent data were plotted from 1950 to 2020 to analyze the publication trend (Figure 1.1). The following sections give an overview of the contents of each chapter for an easy understanding of this book.

Figure 1.1 Number of search results (papers) obtained from PubMed search engine with different keywords: (a) Hydrogel, (b) injectable gel, (c) injectable hydrogels and (d) 3D print hydrogels.

1.2 Introduction to Hydrogels and Their Syntheses

Hydrogels are three-dimensional (3D) networks of polymers, which are crosslinked and consist of hydrophilic polymer chains with the ability to absorb a huge amount of water.³¹ The hydrogels possess the capacity to swell in water; however, these do not dissolve immediately.³² The term “hydrogel” was first reported in 1894 even though it was a colloidal hydrogel consisting of inorganic salts; still, the term has been used consistently from that period.³³ The typical crosslinked hydrogel developed was first reported in 1960, and the polymeric material was poly(hydroxyethyl methacrylate) (pHEMA).³³ These hydrogels were developed mainly for application involving long-lasting contact with the human tissues and were considered to be the first man-made biomaterial used in the human body.³⁴ From this point, the research on hydrogels for biomedical-related applications started gaining momentum largely during the 1970s period. Over the years, the specific goals and aims changed constantly with the evolvement of the hydrogels and their different types through development in polymer chemistry and biomedical technologies. The history of hydrogels was explained as three different generations by Buwalda et al.³⁵ The first generation of hydrogels primarily consisted of gels with varying crosslinking methods by chemically modifying a monomer or polymer through an initiator. During this period, the idea was to create crosslinked materials that had high mechanical properties along with improved swelling properties through simple routes.³⁵

Following this period, in the 70s, the importance of hydrogel shifted to the next level, where stimuli-responsive properties were inculcated in the hydrogels. These second-generation hydrogels were capable of responding to highly specific stimuli such as pH and temperature variations or biomolecule concentrations in a solution. The major advantage of such stimuli responsiveness is in enabling the hydrogels to be triggered for activating various processes such as releasing specific drugs, crosslinking/polymerization of the biomaterials and also to form in situ pores of gel networks.^33,35

In the third-generation hydrogels, the focus shifted to the development of stereo complexed biomaterials and hydrogels linked using physical interactions. These evolutions led to the intensified attention of the scientific people to develop the modern “smart hydrogels”, which has the capabilities to be tuned for obtaining specific properties including the stimuli responsiveness and controllable mechanical and other physico-chemical properties. This area of research is vast and limitless in its perspective application window, as it can be applied to any field from engineering to medical devices and many more.^33,35

One of the pioneering works was reported by Wichterle and Lim on developing crosslinked hydrogels, which had the hydrophilic properties and showed immense potential to be translated as a biocompatible material.³⁶ Such works led to much higher interest for the biomaterial scientists to foster these hydrogels for several years now. In continuation o...

Table of contents

• Cover
• Title
• Copyright
• Contents
• Chapter 1 Overview of Injectable Hydrogels for 3D Bioprinting and Tissue Regeneration
• Section 1: Hydrogel Synthesis and Characterizations
• Section 2: Introduction to 3D Bioprinting of Injectable Hydrogels Introduction to 3D Bioprinting of Injectable Hydrogels
• Section 3: Hydrogel Applications
• Subject Index