Fabrication of Scaffolds for Bone-Tissue Regeneration (a)


Petra Chocholata , Vlastimil Kulda and Vaclav Babuska *
Department of Medical Chemistry and Biochemistry, Faculty of Medicine in Pilsen, Charles University,
Karlovarska 48, 301 66 Pilsen, Czech Republic; petra.chocholata@lfp.cuni.cz (P.C.);
vlastimil.kulda@lfp.cuni.cz (V.K.)

  • Correspondence: vaclav.babuska@lfp.cuni.cz; Tel.: +420-377-593-281

    Abstract: The present article describes the state of the art in the rapidly developing field of bone tissue engineering, where many disciplines, such as material science, mechanical engineering, clinical medicine and genetics, are interconnected. The main objective is to restore and improve the function
    of bone tissue by scaffolds, providing a suitable environment for tissue regeneration and repair.
    Strategies and materials used in oral regenerative therapies correspond to techniques generally used in bone tissue engineering. Researchers are focusing on developing and improving new materials to imitate the native biological neighborhood as authentically as possible. The most promising is a
    combination of cells and matrices (scaffolds) that can be fabricated from different kinds of materials.
    This review summarizes currently available materials and manufacturing technologies of scaffolds for bone-tissue regeneration.

Introduction
Tissue engineering is a relatively new and a very multidisciplinary field. It interconnects many disciplines, such as materials science, mechanical engineering, clinical medicine and genetics [1].
The main objective of tissue engineering is to restore and improve the function of the tissues by preparing porous three-dimensional scaffolds, and seeding them with cells and growth factors [2].
These three things (scaffolds, cells, growth factors) are known as “the tissue-engineering triad”, and this system is set up in an appropriate environment in a bioreactor [3,4]. The term “tissue engineering”, where engineering and the life sciences are interconnected, was introduced in 1988 in the National
Science Foundation workshop as “the application of principles and methods of engineering and life sciences towards the fundamental understanding of structure–function relationships in normal and pathological mammalian tissues and the development of biological substitutes to restore, maintain or
improve tissue function.” Langer and Vacanti used this term in a review article published in Science in 1993 [5].
Tissue engineering uses different techniques and different systems. The simplest approach is delivery of suitable signal molecules (tissue-inducing substances) to the right place. Most techniques rely on cells or cell substitutes, which can replace non-functional cells. The challenges are to preserve
their function and immunological rejection. The most promising are combinations of both cells and matrices, as a matrix can be used in different kinds of materials as a matrix, and there is a tendency to investigate bioactive materials that mimic the native biological neighborhood [6]. This system could be implanted or used as an extra-corporeal mechanism, where cells placed on or within matrix systems can be open or closed (encapsulated). An open system is fully integrated into the body. The cells are anchored in a matrix and the system is implanted into the body. Use of immunosuppressive drugs
or autologous cells is a way of avoiding immunological rejection. A closed system is protected from the patient’s immune system by a membrane that isolates the cells but allows nutrients and waste to permeate [5]. Strategies and materials used in oral regenerative therapies correspond to techniques generally used in bone tissue engineering.

Bone Tissue Engineering
Bone tissue engineering could be a way of repairing bone defects generated from various causes.
This field comprises three main parts in vivo or in vitro—seeding cells, growth factors and scaffold materials [7].
The main target of tissue engineering is to simulate natural behavior. The big advantage of bone tissue is its natural self-repairing, remodeling and regeneration. There is an aim to produce scaffolds able to provide regenerative signals to cells. Scientists try to develop a way of producing scaffolds made of biomaterials that mimic those found in the natural environment, with multi-functional properties, such as improving cell adhesion, proliferation, and differentiation [8].
Bone transplantation is the second most common type of tissue transplantation following blood transfusion. Due to the aging of the population, it is expected to be increasingly in demand [9].
Bone tissue engineering combines biomaterials and cells. In the field of bone regeneration, emphasis has been placed on stem cells [10], particularly in connection with osteoblasts.
Based on principles of modern tissue engineering, craniofacial tissue engineering emphasizes craniomaxillofacial applications and aims to develop biomaterials for regeneration of oral and dental tissues, such as bone, dentin, cementum, periodontal ligaments, mucosa, and salivary glands [11].
Pulp cells were tested on a synthetic polymer scaffold in vivo and in vitro to regenerate the pulp, and it was the fundamental research for pulp-dentin tissue engineering [12].

Regenerative endodontics (RE), a new part of regenerative medicine, aims to treat infection of the dental pulp that can lead to inflammation and even to tissue necrosis. Root canal system treatment may be a common way, but it could lead to re-infection and even to tooth loss at the end. RE tries to discover alternative methods of pulp and dentin regeneration. Cell therapy is becoming a pivotal part
of RE, and human permanent dental pulp tissue stem cells (DPSCs) could be a promising source of stem cells. DPSCs can be accessed easily, and they could be able to differentiate into various lineages (e.g., fibroblast, nerve cells, endothelial cells and odontoblasts) to create new connective tissue [13].
An easy source of DPSCs could be human third molars, due to their high level of clonogenicity and proliferation and ability to form calcified colonies [14]. The main target of RE is to develop suitable scaffolds, including antibiotic mixtures, cells, and growth factors, for pulp-dentin complex regeneration.
Scaffolds could be produced from polymers, both synthetic (e.g., poly(lactic) acid) and natural (e.g., collagen) by various technologies [15].
Guided bone/tissue regeneration (GBR) is the most well-documented technique of periodontal regenerative therapy [16]. GBR, also called “membrane protected bone regeneration” [17], uses barrier membranes in the treatment of alveolar ridge defects and promotes bone growth into tissue defects adjacent to dental implants. Mineralization of the newly formed bone matrix at the GBR region could develop earlier than at the bone-implant interface, and it causes local mechanical stability due to regional variation of interfacial bone properties [16]

Structure and Properties of Bones
3.1. Architecture of Bones
The bone tissue is well organized from macro- to nano-scale structures (Figure 1) [10]. The bone extracellular matrix (ECM) consists of organic components (22 wt %), inorganic crystalline mineral components (69 wt %) and water (9 wt %). Organic components consist of type I collagen, also type III and type IV collagen, and fibrin [18]. In addition, there are over 200 types of noncollagenous matrix proteins (glycoproteins, proteoglycans, sialoproteins, etc.) [9]. Inorganic crystalline mineral components are represented by hydroxyapatite and calcium phosphate. Bone tissue contains the largest amount of calcium in mammals and it can be treated as a ceramic-organic bio-nanocomposite complex [9]. Organic components ensure flexibility, whereas inorganic components ensure strength and toughness [18]. The mechanical, biological and chemical properties and functions of bones depend on the irregular but optimized structure, making bone material heterogeneous and anisotropic, as can be seen at different levels (Figure 1) [18,19].

Figure 1. Different length scales in hierarchically organized bone. The macrostructure creates the overall bone shape and consists of trabecular (cancellous, spongy) bone, 50–90 vol % porosity and compact (cortical) bone, less than 10 vol % porosity [20]. The microstructure (of about 10–500 μm) consists of
the Haversian system, osteons and single trabeculae). The sub-microstructure (of 1–10 μm) consists of lamellae. The nanostructure (a few hundred nanometers—1 μm) consists of fibrillary collagen and embedded minerals. The sub-nanostructure (below a few hundred nanometers of minerals) consists of collagen, non-collagenous organic proteins, and fundamental structural elements.

Two major types of bone structure can be distinguished: trabecular and compact bone. Trabecular bone is formed by a porous trabecular network and bone marrow filling a large inner space. Compact bone is made from inorganic crystalline mineral with a very low number of osteocytes, blood vessels,
etc. Both types of bones are reinforced by collagen fibers. Age, anatomical site and bone quality influence the mechanical properties, the most important of which are strength and elasticity. Porosity and architecture affect the properties of trabecular bone. Compact bone is more resistant to longitudinal stress than to radial, and to compression than to tension [18].


3.2. Osteoblasts, Osteocytes, Osteoclasts and Bone-Lining Cells

During life, two inseparable processes—bone resorbing by osteoclasts and bone formation by osteoblasts—happen alongside remodeling of the skeleton with optimal mechanical integrity. Without integrity, there can be bone loss, especially in the form of osteoporosis [21]. Bone modeling takes place during growing up, as well as in adulthood, in which it maintains bending resistance and function.
A long-term process of bone remodeling replaces damaged bone with new bone and maintains functions. Modeling and remodeling maintain formed bone and participate in repair of bone fracture.
It has been established that about 25% of trabecular and 3% of cortical bone are removed and replaced every year [22].

Marrow stroma is important for regulation of hematopoiesis. Endosteum, a source of mature osteoblasts in adulthood, comprising bone-lining cells, is important for the regulation of bone formation.
Periosteum consists of two layers, a fibrous layer formed by collagenous tissue and a cambium layer containing a large number of cells. Cells in the cambium layer are activated during bone regeneration and fracture repair. Osteocytes (osteocyte perilacunar matrix) are present together with vasculature in a lacunocanalicular system (not mineralized), generating bone surface and participating in the production of ECM proteins that are important to phosphate metabolism and mineralization.
An overview of bone ECM components can be seen in Figure 2 [21].

(TO BE CONTINUED)

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