A comprehensive review on polymeric hydrogel and its composite: Matrices of choice for bone and cartilage tissue engineering

Abstract

The need of tissue and organ for transplantation to repair or replace damaged tissues is significantly higher than the availability of donated organs. Tissue engineering that develops functional substitutes for damaged tissues and organs via employing a combination of 3D biomaterials, supportive bioactive molecules, and/or living cells followed by in vitro culture and/or in vivo implantation, therefore, has attracted much attention in engineering the substitutes. Among 3D biomaterials, hydrogel materials have been extensively explored as matrices for skeletal regeneration because of their biocompatibility, tailorable mechanical properties, flexibility in fabrication, and ability to encapsulate cells and bioactive factors for their sustained, localized and controlled presentation. This review focuses on polymeric hydrogels and theirs composites for both bone and cartilage regeneration, including required properties, design and fabrication, functioned as bared biomaterials or delivery vehicles of bioactive molecules and/or cells together with remaining challenges and future perspectives, emphasizing on the last few years.

Introduction

Injuries in bone and cartilage affect millions of people each year with numerous contributed reasons, including congenital anomalies, skeletal diseases, surgical resection, and trauma [1], [2], [3]. Unfortunately, the self-regenerative capacity of cartilage is limited, especially in the elder people, due to its thick extracellular matrix (ECM) and aneural, non-lymphatic, and avascular intrinsic nature, which lead to the lack of blood supply, the access of progenitor cells as well as regenerative factors to the injury sites [4]. Unlike cartilage, bone normally exhibits the ability of self-healing upon injury due to its highly vascularization, however, they fail to regenerate and repair spontaneously by itself in cases of pathological and massive bone fractures such as non-union fractures, tumor ablations, maxillofacial trauma, or intervertebral disk injury [5], [6], [7]. While various clinical treatments have been established for the repair of bone and cartilage, those are normally accompanied with long-term, complicated processes and the regenerated tissues may possess different structures and functions compared to the native tissues. For instance, autologous bone grafting, a gold standard for bone repair, and autologous chondrocyte implantation (ACI), the only FDA-approved technique for cartilage regeneration, still retain several limitations, such as limited availability of donor tissues, donor site morbidity, and invasive surgical procedure [8], [9]. In addition, autologous bone grafting failure rates in certain sites could be up to 50% in difficult healing environment [10]. Allograft and xenograft, which offer even more obvious drawbacks compared to autograft, also have to face with many complicated issues, such as disease transmission, infection risks, shortage of donor tissues, and prevalence of late rejection [9], [10], [11]. Recently advanced approaches, such as solid biomaterials implantation (metals or ceramic) or three-dimensional (3D) printing of solid materials, are low biocompatible and difficult in fitting to the size and shape of the defects [12]. Therefore, skeletal tissue engineering (TE) that develops functional substitutes for damaged bone and cartilage is emerging as an alternative and innovative solution [13], [14].

Polymeric hydrogels are three-dimensional (3D) cross-linked networks that appear to be ideal biomaterial scaffolds for TE due to their good biocompatibility, biodegradability, highly porous framework, high water content, controllable physical properties, and flexibility in fabrication, and thus provide appropriate artificial support and interaction with the natural ECM [1], [15], [16], [17], [18]. Hydrogels can be engineered into almost any shape and size or directly injected to fit irregular defect sites (Fig. 1) [19]. In addition, organic and/or inorganic fillers could be functionalized to form hydrogel composite for improving the hydrogel properties and performance in certain applications [2], [20], [21], [22], [23], [24], [25], [26], [27], [28]. In TE, polymeric hydrogels as well as hydrogel composites could be used as simply supported biomaterial scaffolds, encapsulation and control the delivery of regenerative molecules, and/or encapsulation cells to control the proliferation and differentiation (Fig. 1) [21], [29], [30], [31]. They can facilitate the retention, adhesion, migration, proliferation, and differentiation of chondrocytes, osteoprogenitor cells and other cells for skeletal tissue repair.

Hydrogel materials for TE, particularly for bone and cartilage regeneration, have received remarkable interest because they demonstrated many opportunities. However, there are also numerous remained challenges. Previous reviews of hydrogels that are specifically used for skeletal TE mostly focus on several types of materials and fabrication methods. This work aims to reports a comprehensive review of polymeric hydrogels and their composites which can be used for both bone and cartilage regeneration as these tissues are normally connective tissues which made up of cells embedded in connected extracellular matrixes and, in some cases, required simultaneously engineering. In addition, the required properties of hydrogel materials for bone and cartilage, their design and preparation, such as polymeric sources and crosslinking chemistry will be presented. The potential application of these polymeric hydrogels and their composites as bared biomaterials or delivery vehicles for regenerative molecules and/or cells in bone and cartilage TE and the remaining challenges and future perspectives will also be discussed, with an emphasis on the last few years.