Bone Repair Strategies: History
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Subjects: Materials Science, Biomaterials
Contributor:
Yao Zhao
,
Sinuo Zhao
,
Zhengxin Ma
,
Chunmei Ding
,
Jingdi Chen
,
Jianshu Li

In comparison with the bone tissue engineering (BTE) strategy, the facilitated endogenous tissue engineering (FEBTE) strategy as a novel practical approach tries to eliminate time-consuming and costly tedious process: tissue harvest, cell isolation and ex vivo co-culture with a scaffold. Based on this, the FEBTE strategy as a facile and effective strategy, is booming in bone tissue regeneration. Particularly,  chitosan (CS)-based scaffolds with versatile qualities including good biocompatibility, biodegradability, and tunable physicochemical and biological properties could recruit endogenous stem cells homing and differentiation towards lesion areas during  the process of bone repair. 

  • facilitated endogenous tissue engineering
  • chitosan
  • bone repair
  • bioactive scaffold
  • functional design

1. Introduction

Bone tissue, as a dynamic living tissue, possesses a complex hierarchical structure. It plays an important function in body support, tolerance of force damage and the protection of internal vital organs, as well as providing a stable circulation environment for the bone marrow [1][2][3]. Normally, bone has a certain regenerative potential over time in the face of minor injuries [4][5]. In plenty of surgical trauma cases, however, once the critical-sized lesion is generated, it is difficult to achieve the effective repair of the defect tissue by the mere physiological regulation of an organism [6][7]. Clinically, exogenous implants are required to guide the repair of critical-sized bone defects. As the golden standard, auto/allogeneic transplantations have achieved positive effects, while limited donor sources, immunogenicity and the risk of infection caused by the second surgery restrict their widespread application [8]. Moreover, bone tissue engineering (BTE) consists of three important parts including a scaffold, cells, and growth factors, which achieves a good bone matrix simulation and overcomes the limitations of these transplantations mentioned above [9][10]. However, these traditional tissue engineering procedures are cumbersome, inconvenient, and time-consuming. Generally, tissue harvest, cell isolation, and ex vivo co-culture with a scaffold, as well as two invasive surgical procedures are included.
Inspired by an organism′s own repairing potential, facilitated endogenous bone tissue engineering (FEBTE) has been proposed as a more feasible approach to guide bone regeneration [11][12]. In comparation with traditional BTE, this strategy does not require the ex vivo culture of autologous cells and thus avoids the invasive surgical procedures with high risk [13]. In order to achieve the equivalent repair effect to BTE, a bioactive scaffold is usually employed in FEBTE strategy to in situ activate the intrinsic regenerative potential of native bone tissue and accelerate the tissue healing [14][15]. Therefore, the scaffold with appropriate material composition and bone-like structure is the key to recruit endogenous stem cells and growth factors to the damaged area in the organism. Some artificial metal/polymer implants (e.g., titanium and polymethyl methacrylate) were employed in this method. Nevertheless, the satisfactory host–material interface interactions and biosafety remain a challenge [16][17][18][19]. Subsequently, scientists have focused more on natural polymers such as bacterial cellulose, silk fibroin, and hyaluronic acid, etc., because many of them have good biocompatibility and non-immunogenicity to meet the requirements of in vivo transplantation [20][21][22]. However, these materials still have undeniable shortcomings; for example, pure cellulose shows a poor biodegradable ability in the physiological environment and poor osseointegration, which limits its further routine use in bone tissue engineering [23]. In addition, the weak mechanical properties and complicated purification process of hyaluronic acid, as well as the high production cost and limited source of silk fibroin, also weaken their use in bone tissue engineering (especially load-bearing bones) to a certain extent [24][25].
As a renewable source, chitosan (CS) is a naturally derived polysaccharide mainly produced from the exoskeleton of marine crustaceans [26], with a molecular structure and biological activity similar to the bone extracellular organic matrix [27]. The excellent biodegradability, biocompatibility and nontoxicity of CS have made it widely used in the field of bone repair [28][29][30]. Contrary to many synthetic materials such as polycaprolactone (PCL) and polylactic acid (PLA), the hydrophilic feature of CS can improve cell adhesion and growth on the scaffold surfaces [31][32]. Particularly, owing to the existence of a large number of amino and hydroxyl groups on the surface of CS, it is easy to be chemically modified and extensively designed [33][34][35][36]. For example, CS cross-linked with collagen (Col) showed better mechanical strength than pure Col scaffold, and the high porosity of CS/Col scaffold provided adequate space for the growth and differentiation of MC3T3-E1 cells [37]. Moreover, CS-based scaffolds can also act as a carrier to effectively control the release of osteo-inductive molecules, such as drugs [38][39], proteins [40][41], and peptides [42], etc., and then facilitate osteogenesis. Inspired by the biomineralization of natural bone, CS is often combined with other molecules to act as a mineralization template to induce the in situ crystallization of inorganic functional particles, such as bioactive hydroxyapatite (HAP) and magnetic ferric tetroxide (Fe3O4)[43]. Therefore, the versatile designability of CS-based scaffolds renders them promising candidates in the process of endogenous bone repair.
The recent advances in chitosan-based scaffolds for facilitated endogenous bone regeneration (Figure 1). Initially, two bone repair strategies, FEBTE and BTE, are introduced and compared. Subsequently, CS sources, CS-based composite scaffolds and their fabrication techniques are briefly introduced. Furthermore, the functional designs of CS-based scaffolds in bone endogenous regeneration, including the loading of biomolecules, hybridization with inorganic nanomaterials and exogenous physical stimulation are highlighted and discussed in detail. Finally, the major challenges and further research directions of CS-based scaffolds are also elaborated.
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Figure 1. Multifunctional design of chitosan-based scaffolds and the application in facilitating endogenous bone regeneration.

2. Bone Repair Strategies

2.1. Traditional Bone Tissue Engineering

Although auto/allogeneic transplantations, as the golden standard in the clinical setting, have achieved positive results in critical-sized bone defects repair, the limited donor sources, immunogenicity and the risk of infection caused by the second surgical procedure limit their widespread development [44][45]. In order to overcome the drawbacks of auto/allogeneic transplantations, the emergence of BTE has been warmly welcomed in the last three decades [46]. Briefly, the BTE strategy mainly consists of three parts: a scaffold, cells and growth factors [47]. As shown in Figure 2, the procedure begins with the isolation and harvest of target autologous tissues, then resuscitation and expansion of stem cells in specific culture equipment. After reaching a sufficient number, the cells are seeded into a prefabricated scaffold for co-cultivation in vitro. Simultaneously, suitable growth factors and nutrients are continuously added to provide beneficial conditions. Finally, the differentiated new tissues are implanted into the patient’s lesions to further interact with the host tissue, and finally promote defect tissue healing in vivo [48][49][50].
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Figure 2. Comparison of two bone repair strategies. Traditional bone tissue engineering (BTE) needs tissue harvest, cell isolation and co-culture with a scaffold ex vivo, while facilitated endogenous bone tissue engineering (FEBTE) avoids these tedious and risky procedures by using a bioactive scaffold.
Generally speaking, the success of relevant clinical trials has validated the feasibility of this strategy. However, judging by the collapse of several well-known companies specializing in this field, this strategy is not cost-effective [51]. It is not hard to see that the actual operation process of tissue engineering is complex and costly. The complexity mainly lies in the co-culture of autologous cells and scaffold, as well as the usage of two invasive surgical procedures. In addition, the high cost mainly results from ex vivo culture media, sera, growth factors and the bioreactor, as well as the sterile and delicate culture environment. Furthermore, the quality of engineered products is also uneven.

2.2. Facilitated Endogenous Bone Tissue Engineering

The issues of complexity and high cost need to be addressed if BTE is to avoid becoming an expensive therapy available only to the wealthy. Specifically, we need to develop large-scale automated and replicable production systems as alternatives to labor-intensive production process. In view of the organism’s own repair potential, the biological microenvironment is used as a bioreactor to simplify the tedious process of BTE and finally achieve bone healing in situ. Therefore, the facilitated endogenous bone tissue engineering (FEBTE) strategy has emerged [11].
In comparison with the BTE strategy, the FEBTE strategy as a novel practical approach tries to eliminate time-consuming and costly tedious process: tissue harvest, cell isolation and ex vivo co-culture with a scaffold. Interestingly, this strategy only requires the implantation of a bioactive scaffold into the bone defect sites to induce the defect tissue repair by itself (Figure 2). The bioactive scaffold functions as a “gravitational field” to attract and positively recruit endogenous stem cells and growth factors to the damage site, and then promotes stem cells proliferation and osteogenic differentiation, thereby repairing bone defects [15]. Therefore, based on the convenience and cost-effectiveness of the FEBTE strategy, it has successfully attracted extensive attention in the field of scientific research [14][52]. Among them, the most important and key point is to construct a bone repair scaffold with excellent osteo-inductivity.
 

 

 

 

 

This entry is adapted from the peer-reviewed paper 10.3390/ph15081023

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