3D hydroxyapatite scaffold for bone regeneration and local drug delivery applications

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Abstract

Bone tissue engineering is the technology of healing bone defects in critical clinical conditions using functional tissue-engineering substitutes. Hydroxyapatite (HAp), as a biomaterial, received extensive attention for biomedical applications in the last 15 years. HAp has been utilized systematically as a filling material for bone defects, artificial bone grafting, and as a scaffold material in prosthesis revision surgery. In this brief review, we discuss on the fundamental aspects of porous HAp scaffolds, which define their utility in bone-tissue engineering and orthopedic drug delivery applications. The review contains six sections. Section 1 provides a brief introduction on tissue engineering, history of using bio-ceramics in tissue engineering, and the present state-of-the-art scenario of tissue engineering. In section 2, we provide a brief survey of biomaterials of different kinds utilized for tissue engineering. Section 3 provides a brief review on conventional scaffold fabrication techniques and their advantages and disadvantages. In section 4, the essential physio-chemical and biological cues to the development of HAp scaffolds and their compatibility with the surrounding cells and tissues, along with their application potentials for drug loading and site-specific drug releasing are discussed. Sections 5 & 6 provide the prospects of HAp scaffolds in biomedical applications, and conclusions, respectively.

Introduction

Tissue engineering is an interdisciplinary field, which applies the principles of science and engineering for the development of biological substitutes that restore, maintain, or improve tissue functions. Tissue engineering integrates cell biology, medical science, materials science, and biological engineering. As has been stipulated by Hench et al. [1], biomaterial research desires to focus on rejuvenation of tissues instead of replacement. In this context, Kokubo et al. [2] investigated several novel bioactive materials of different mechanical properties. The broad areas of tissue engineering application are orthopedics, skin development, cartilage regeneration and reconstruction of neurons and organs. The evidence of pre-historic practice of tissue engineering is evidenced in ancient manuscripts, paintings, and body part remainings such as skeleton, mummy, etc. The famous painting “Healing of Justinian” (278 AD) depicting the transplantation of a homograft limb onto an injured soldier, is an early instance of the vision of regenerative medicine. The history and development of biomaterials since ancient civilizations dated beyond the past 4000 years has been described nicely by Dorozhkin [3]. At the beginning of the modern era (twentieth century), Plaster of Paris was the most popular bio-ceramic. The knowledge of toxicity and invention of aseptically surgical techniques boosted the practice of artificial prosthetic implantation. Body systems are made of organs and tissues. Cells are the building blocks of tissues. Tissue represents the cellular organizational level intermediate between cells and a complete organ. Different types of tissues such as epithelial, connective, nervous, muscle tissues, etc. exist in the animal system. When it comes to the repairment of damaged tissues, cell growth is often uncontrolled, hindering the healing process. One of the most convenient approaches adapted for controlled tissue engineering is the use of structural support to facilitate and guide the healing and growth of damaged body parts. In fact, biological cells can be implanted or 'seeded' into an artificial structure, known as “scaffold”, capable of supporting three-dimensional tissue formation. The scaffold is a porous structure, adequate for cell colonization, and formation of new tissues through the reproduction of specific cells. Until 2008, an estimated 800,000 hip and knee arthroplasties have been used annually in the United States and Europe annually. In the literature, the properties and function of biomaterials have been discussed frequently in the context of hip endo-prosthetic implants made of popular bio-ceramic materials such as alumina, yttria stabilized zirconia (YSZ) and calcium phosphates (e.g. hydroxyapatite) [4]. Bioactive composite materials have also been tested and experimented rigorously for tissue replacement purpose during the past few decades, with special interest on some of them [5,6]. To fabricate scaffolds for tissue engineering, a comprehensive study is needed around the ideal material with necessary characteristics. An ideal scaffold material should have following properties for utilization in tissue engineering: (i) Biocompatibility is an important characteristic of scaffold materials which deals with inflammatory response or toxicity in the patient. The scaffold materials must bear nontoxic and non-inflammatory characteristics. The scaffolds made of such materials must sustain cell adhesion and proliferation. (ii) Interconnected porous morphology is an essential parameter for the design of porous scaffolds, which are responsible for the nutrient and essential body fluid supply to the transplanted and regenerated cells. Scaffolds with interconnected pore structures enhance nutrient and fluid diffusion rates and allow a better vascularization. (iii) Adequate mechanical properties with enough mechanical strength and stiffness to support the tissue under growth, until the newly grown tissue acquires strength to support itself. (iv) Biodegradability is an optional property for different types of scaffold. Most of the scaffold materials manifest degradation properties, leaving the space for new cell growth. Scaffold materials should have the capacity of breaking and dispersing in the biological fluid, even though there is no proof of elimination from the body due to macromolecular degradation. (v) Appropriate surface chemistry for cell attachment, proliferation, and differentiation makes a scaffold to be a successful prosthetic device for biomedical application. For example, some cells–osteocytes are exclusively located on the surface of the bone matrix. Cell adhesion in this case is essential, as it will allow further cellular functions such as spreading, proliferation, migration, and biosynthetic activities. Moreover, scaffold materials should allow the cells to differentiate blood vessels from other tissues at their surfaces to heal the traumatized organs. Biomaterials utilized for scaffold fabrication can be principally categorized in four major groups, such as: (1) ceramics, (2) natural or synthetic polymers, (3) metals, and (4) composites of these three or either two of them (Table 1).

Till date, different types of materials have been used to treat diseased, damaged or traumatized bone tissues. These materials include polymers (natural and synthetic), metals, ceramics and their combinations. Bio-ceramics are highly stable materials with superior bioactivity, which make them attractive for tissue engineering applications. On the other hand, biopolymers can be natural or naturally derived (e.g. collagen, chitosan fibrin etc.), and synthetic (e.g. poly (glycolic acid) (PGA), poly (lactic acid) (PLA), and their copolymers PLGA] [8]. Biomaterials synthesized or processed from natural origins have potential advantages due to their good biocompatibility, along with cell adhesion and function supports [16,18,19]. However, sometimes a direct use of naturally derived biomaterials is not possible due to immunogenicity or pathogenic microbe contamination, which requires further post-processing [[20], [21], [22]]. In this respect, synthetic materials have advantages due to their reproducible and tunable properties without microbial contamination. These are the reasons for the wider usage of synthetic materials in biomedical and tissue engineering applications in comparison to their natural counterparts [23,24]. Collagen is a natural fibrous protein, which is the main component of the extracellular matrix of mammalian tissues such as skin, bone, cartilage, tendon, ligament, etc. As has been demonstrated by Mizuno et al. [25], bone marrow stromal cells can differentiate osteoblasts in type I collagen matrix under in vivo conditions. On the other hand, use of hyaluronic acid-based polymers as cell carriers for tissue-engineered repair of bone and cartilage has been presented by Solchaga et al. [9]. Use of bio-degradable synthetic polymers based scaffolds such as PEG-based hydrogel scaffolds have been reported by several research groups [26] for bone regeneration. In fact, development of novel biodegradable polymeric biomaterials for tissue engineering applications is a great challenge in current biomedical research. Development of polymer based scaffolds with controlled architecture for cellular attachment and function is still in its initial stage, which needs innovative and technologically advanced therapeutic approaches [27]. However, not all is good with the use of polymer in biomedical research. The main drawback of biopolymers is their high degradability. They can be degraded very easily, releasing acidic products, which can trigger aseptic inflammation reactions and swelling [28]. The other limitation of polymeric scaffolds is their mechanical properties such as low tensile and compressive stresses, and inferior wire properties [29]. These disadvantages of polymer-based scaffolds, especially for load-bearing applications (dental and orthopedic surgery), could be overcome by utilizing biocompatible metallic materials (pure, alloy or composites). Standard surgical implant materials include stainless steel 316 L (ASTM F138), cobalt-based alloys (mainly ASTM F75, and ASTM F799) and titanium alloys; Ti–6Al–4V (ASTM F67 and F136) being the most utilized one. However, the main disadvantage of metallic biomaterials is their lack of surface biological recognition. The limitation could be overcome by implementing surface coatings or other surface modifications, preserving their mechanical properties. To improve inter-cellular communications, metallic biomaterials can also be organized inside porous scaffolds and suitable cellular ligands with signaling factors attached to the scaffold surface [10]. The biocompatibility of metal-based biomaterials has also been compromised due to the release of toxic ions and/or particles through their corrosion or wear, which might induce allergic reactions and inflammation of the target [11]. However, the problems can be avoided through appropriate surface treatment of the fabricated scaffolds or coating them by appropriate material.

Finally, hybrid or composite materials are another important class of materials, utilized for scaffold fabrication with ample success, especially as artificial joints and bone implants with the capability of stimulating specific growth factors and drug loading at molecular level. The most popular composites utilized for biomedical and therapeutic applications so far are made of polymer/bio-ceramics, and polymer (synthetic or natural)/metals. Novel metal/ceramic/polymer hybrid materials have also been proposed for the fabrication of load-bearing scaffolds [30]. In fact, in some critical clinical cases, tailored designed composite scaffolds are necessary for the reconstruction of structural diseases and bone defects [31]. Nevertheless, the mechanical property requirements for hard tissue repair are difficult to satisfy using porous polymer/ceramic composites [32].

Section snippets

Design, fabrication, and mechanical characterization of HAp scaffolds

Different techniques have been employed for manufacturing scaffolds for tissue engineering applications. Among them, the most common ones are computer-aided rapid prototyping (RP), injection or compression moulding, gel-casting, compacting, 3D printing, etc. [15,[33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48]] Computer-aided RP and 3D printings are the most advanced technologies used for the development of sophisticated scaffolds. Both the

Clinical applications of HAp scaffolds: drug loading, drug release, in vitro, in vivo studies, medical application

Although HAp scaffolds fabricated using macroscopic HAp particles have been time-tested for their biomedical applications, recent progress on the fabrication of HAp nanostructures revolutionized this effort, resulting in the fabrication of nano HAp scaffolds with higher porosity, hardness and higher drug holding capabilities [66]. As in drug delivery systems a slow, controlled, local and sustained release of drug at the affected site is highly desirable, HAp scaffolds with high porosity,

Prospects of HAp in biomedical applications

Although HAp biomaterials have been widely investigated, there remain several challenges to be consider before their clinical applications. The development of multifunctional properties with therapeutic ion release also has great potential for biomedical application. Doping of different metals such as Au, Zn, Ag, Mg, Mn, Sr, Cu, Fe, Eu, Gd, etc., might be useful to provide smart strategies for in situ therapeutic application. The HAp bio-ceramics could also be useful towards therapeutic as well

Conclusions

Calcium phosphate-based bio-ceramics are the popular biomaterials due to their excellent biocompatibility and bioactivity driven by their compositional similarities with human bones and teeth. Porous scaffolds based on HAp have been widely used for hard tissue engineering due to its similar structure to the natural cancellous bone. Several techniques such as gel-casting, injection press moulding, solvent casting, freeze-drying, etc. have been utilized to fabricate HAp scaffolds of different

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

SM is thankful to Instituto de Física, Benemérita Universidad Autónoma de Puebla (BUAP) Puebla, and PRODEP-SEP, Mexico, for providing postdoctoral fellowship (Offer No. DSA/103.5/15/8164). Partial financial supports extended by VIEP, BUAP (Grant # 100236944-VIEP 2018) and CONACYT, Mexico (Grant # INFR-2014-02-230530) are acknowledged.

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    Present address: Department of Biomedical Engineering, Nanobiomedicine Laboratory, Pukyong National University, 45, Yongso-ro, Nam-Gu, Busan, 48513, South Korea.

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