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Nanomaterials for Bone Repair and Regeneration Report

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Updated: Apr 9th, 2022

The field of medicine has experienced notable development in medicine and technology integration. Medical scientists seek new methods for offering better services to patients. Bone reconstruction is an area of medicine that has shown remarkable technological growth. This literature review discusses the use of nanomaterials for bone repair and regeneration.

The structural composition of bones is necessary for successful bone repair. Even though the functional needs for skeletal bones differ by position, each bone offers mechanical rigidity and support. Bone rebuilding usually necessitates large amounts of donor tissue and complicated multistep surgical processes for the achievement of the necessary aesthetic and functional outcomes, for example in the maxillofacial region, where reconstructions are complex yet necessary to increase quality of life in post injury. Medical options for rebuilding an absent bone part are bone from autologous vascularized bone segment transfers, cadaver bones, utilization of soft tissue for the reconstruction of bony deficiency, grafts, application of bio-materials, for example titanium, ceramics, and hydroxyapatite (Laurencin, Khan & El-Amin 2006).

Allografts, for example cadaver bones, are susceptible to risk infection and have low union rates with the neighbouring tissue. Bone mixing is higher in integration despite the disadvantage of donor site injury and incomplete tissue availability. When autologous soft tissues are used, reconstruction has low support and strength, frequently resulting in low functionally outcomes when linked to bony regeneration (Cheng et al. 2005; Miller 2000).

Currently utilized synthetic implants have limitations, including fracture, fatigue, low- integration levels to the host tissues, infection, and extrusion. Therefore, it is necessary for additional bio materials with recovery ability to complement bone generation in an organized manner and also support assimilation into the original tissue at the injured segment. During bone graft implants, there are various important concerns for successful bone reconstruction, which include “form, function, fixation and formation” (Anderson et al. 1998, p. 164).

Form describes the aptitude to follow the 3D (three-dimensional) pattern of the injury. The tissue should substitute the role of the bone by complementing the automated characteristics of the material to the functions of the original bone and including the ability to transfer mechanical signals, which can control cell and matrix biology and enhance regeneration and remodelling. Formation is the ability to stimulate osteo-conductivity and is influenced by porosity, diffusivity, permeability, and cell incorporation or bioactive dynamics (Rios et al. 2009).

An important balance must be sustained throughout the recovery of load-carrying tissues from injury, in order to sustain the mechanical strength. This requires the level of degradation in the implanted biomaterial to be equal to the level of new matrix removal. Fixation describes the graft’s ability to combine with neighbouring tissues.

Design complexity increases with every additional design criteria however it is important to embrace each factor for clinically applicable grafts. Researchers find it complex to investigate the modelling and production of biomaterial structures that will substitute the natural bone elements without necrosis. The configuration, construction, and mechanical features of the matrix or scaffold are significant to engineer grafts that may balance the dilapidation associated with remodelling and deposition of reconstructed tissue.

The biological and structural features also influence the previous inflammatory reaction, cell repositioning, accumulation of neo-extracellular matrix, dilapidation of the biomaterial structures, new extracellular matrix growth, mineralization, vascularization, and functionality characteristics at the reconstructed or restored tissue points. Different methods of bio material construction have been created to cater for the clinical requirement for bone healing, regeneration and renewal (Rios et al. 2009).

Both structural design and chemical configuration are constraints that have been considered for managing bone formation complexities in vivo and in vitro (Christenson 2007; de Oliveira et al. 2007; James et al. 2011). The most recent method of engineering biomaterial architecture is constructing nano-meter scale characteristic size material in a macro-scale defect size-based model. This literature review summarizes current empirical designs of nano-biomaterials, cell interactions with these nano-composites or nano-materials, and bone reconstruction utilizing the nano-designed bio-tissues.

Modelling of nanobiotissues for bone tissue reconstruction

Ordered classification of original bone Extracellular Matrix (ECM)

Bones are composite structures made of inorganic (mineral) and organic (protein) parts. Macroscopically, bones comprise of dense crust of cortical bones that offer support and protection, and a permeable cancellous bone tissue at the two edges, capable of optimizing weight transmission and minimizing friction at the end joints. The cortical bone comprises of repeating osteon components, whilst the cancellous bone comprises an interconnecting structure of trabeculae and bone marrow filled open spaces. The osteon and trabeculae units comprise of collagen fibres.

20 to 30 concentric fibre layers (lamellae) are located in the osteons, and positioned at approximately 450 around the principal canal, containing nerves and blood vessels. The 100 to 2000nm fibres comprise collagen fibrils and the tertiary composition of collagen fibrils comprises a 67nm periodicity and 40nm openings within collagen particles (Rho, Kuhn-Spearing, & Zioupos 1998). The hydroxyapatite crystals are combined in the gaps within collagen particles and increase bone rigidity (Currey 2002). Bone structure properties are significantly dependent on the organization and structure of the cells and ECM, where ECM organization is hierarchical and covers various linear magnitude orders. Therefore, reconstruction and repair of bone defects necessitate advanced approaches that are responsible for all scales in the hierarchy.

Biomimetic approaches in bone tissue reconstruction

According to the gold model of autologous bone graft, the model contracted bone implant must be “osteoinductive, osteoconductive and osteogenic” (Laurencin et al. 2006, p. 52). Osteoinductive scaffolds provide spatial, bio-chemical, and physical stimuli to instigate stem cells or progenitor cells towards osteoblastic family. Osteoconductivity needs biocompatible implants to encourage the attachment, migration, survival, and supply of osteogenic cells. Osteogenic implants comprise of progenitor or osteogenic stem cells for bone redevelopment.

To satisfy these criteria, bone tissue reconstruction uses a biomimetic approach which may comprise biomaterial supports, physical and biochemical stimuli, vascularization, stem cells, and recapitulating the ordered construction of original ECM to produce functional bone tissues. Such biomimetic efforts comprise selecting bio-materials within the original bone structure, constructing poly-scale models in scaffold particularly with nanoscale elements, and integrating growth factors, stem cells and/or vascularization to offer a bio-mimetic opening for instigating bone reconstruction and regeneration. This review focuses on mirroring three-dimensional organization of bone construction with tissue modelling at the nano-phase.

The construction of biomaterial supports is vital to the functionality of the supports. The final properties of materials are influenced by the choice of tissue and processing strategy. Traditional tissue reconstruction methods apply a downward flow method to reconstruct the macro- and micro phase features of original tissues, nonetheless these traditional supports ignore the nano scale structures and features that cells are familiar with interrelating at cell–environment interface, and are vital to controlling cell functions, including migration, proliferation, and ECM regeneration (Benoit & Anseth 2005).

These concepts usually fail due to insufficient tissue renewal as a result of various complications, such as unwanted local tissue reactions, for instance acute inflammatory reactions owing to macrophage extravasation, neutrophils, and adhesion, external cell growth, and fibrous capsule development (Mathur et al. 1997; Murugan & Ramakrishna 2005).

To summarise the hierarchical arrangement of original ECM, one method is to integrate nano-scale characteristics in the spatial support design. Generally, nano-tissues are defined as materials with plainly described characteristics between 1 and 100nm, including nano-spheres, nano-crystals, and nano-fibres. Since normal collagen fibres fall within the range of 50–500nm, this review considers fibres in this submicron range and nano-tissues.

Unique characteristics of nanocomposite/ nanomaterials for bone tissue regeneration

During the early stage of implantation, biomaterials need to offer structural support to the injured site as the bone material redevelops, requiring support with high original compressive strengths. Likened to typical tissues, nano-tissues offer exceptional characteristics. The availability of nanocrystals or nano-tubes in complex materials for bone tissue construction improves the mechanical characteristics of the support (Xu, Weir & Simon 2008). Also, matrix rigidity is an important factor in bone tissue reconstruction. Matrix rigidity is responsible for mesenchymal stem cells obligation to osteogenic diversity (Engler et al. 2006; Rowlands, George & Cooper-White 2008; Saha et al. 2007). For instance, collagen covered poly-acrylamide creams with an elastic modulus of 25–40kPa supports osteogenic separation of MSCs (Engler et al. 2006).

A single layer of tissue will develop onto implant shells due to adsorption of proteins available in biological fluids from seconds to minutes. The characteristics of the material surface (chemistry, charge, etc.) will determine the adsorbed proteins since proteins comprise diverse amino acid mixtures with widely diverse characteristics (chemical structure, charge, and hydrophilicity/ hydrophobicity). These external changes have been reformed to the entire scaffold through the development of nano-material-based supports.

Cellular reactions to nano-materials, including cell attachment, propagation, and diversity, have been indicated to be influenced by the existence of nanostructures (Chen, Smith & Ma 2006; Woo, Chen, & Ma 2003). Adapted nano featured shells show higher external wettability and energy, which causes a higher level of cell adhesion and protein adsorption (Khang et al. 2008; Webster 2001; Zhang et al. 2008), and eventually affects cell spatial growth (Lim et al. 2008).

Numerous research studies have indicated that nano textured exteriors enhance mineralization and improve in vitro osteo-genesis (de Oliveira & Nanci 2004). The roughness of the nano-phase prevents fibroblast function (Mustafa et al. 2005) improves both osteoclastic and osteoblastic reactions. When external characteristic size reduces from normal to nano-phase, aqueous exchange angles reduce by 300%, which results in higher wettability (Webster et al 2000).

PLGA (Poly-lactic-co-glycolic acid) compound structures comprising titanianano-particles exhibited a higher hydrophilic level than those comprising normal-sized titania, which led to higher osteoblast adhesion (Kay et al. 2002). Spatial nano-fibrous PLLA (poly-L-lactic-acid) gain higher amounts of protein, including vitronectin and fibronectin, than solid pore shells.

Numerous bonding procedures contribute to the adsorption of proteins, including positioning and ability to easily revolve. Higher vitronectin adsorption was noted on nano-phase ceramics, and it was seen to be unfolded to a higher extent to reveal more osteoblast adhesive epitopes than the molecules on normal ceramics. This cell bond process, due to shell characteristics, was also seen on nanophase ceramics in fibronectin (Vance et al. 2004). Generally, nano-featured surfaces offer a greater surface area that influence protein bonding characteristics and increases cell adhesion.

Integrins cover the cell tissues, connect the cytoskeleton to the ECM, and contribute in regulating osteo-blast reaction to nano-materials. Nano-materials improve integrin manifestation in osteoblasts and also contribute to integrin clustering/bonding causing intracellular signalling pathways (Webster et al 2000).

Fabrication and use of nano-biomaterials for bone tissue construction and renewal

Modelling bone structure and form using nano-composites

Nano-composts and nano-biomaterials have been advanced with the use of various strategies and materials to model architecture and composition of normal bones. Bone tissues may be grouped as nano-composite comprising protein and firm inorganic constituents. Model bone scaffold regeneration has yet to be modelled wholly from bioactive ceramics or bioactive polymers. Ceramics are fundamentally inelastic, delicate and polymeric and do not have the strength to maintain the mechanical forces related with regular bone performance. Composites are potential bone graph material because they integrate the characteristics of different materials. For instance, a polymer–ceramic composite integrates the mechanical features of ceramics with the flexibility and ease of polymer scaffold production.

The composites may be modelled using polymer creation methods to create nano-scale systems in the composite, such as nano-molecules, or nano-fibres. Both in vivo and in vitro research studies have indicated their prospects for bone regeneration.

Choosing Polymer for nano-composites

Polymers are broadly utilized for medical purposes owing to their design, surface flexibility, bio-compatibility, and general group accessibility. They may be grouped as non-biodegradable or biodegradable, and may be synthetic or obtained naturally. Several factors influence the effective choice of polymers. Firstly, polymers should possess mechanical characteristics compatible with bone matter. Polymer degradation proportions should also compete with the remodelling and deposition amounts of new tissue; decomposition and polymer products should not be toxic and should curtail immune reaction.

Ceramic and ceramic composites

Ceramics, for instance silicate, tricalcium phosphate (TCP), and phosphate bio-glass, are used for orthopaedics owing to their significant compressive strength and rigidity as well as optimal biocompatibility. Such materials may be categorised as bio-inert, bio-active, and bioreabsorbable. Zirconia and alumina have been in use for a long time for orthopaedic purposes, especially in the area of femoral heads in whole hip reconstruction. TCP is a broadly utilized bioreabsorbable bone implant for light-weight bearing orthopaedic functions (Bohner 2000).

Another material used for bone implants is HA. The choice of HA is due to its structural similarity with natural bones, leading to osteoconductive features and creation of strong bonds with neighbouring natural tissues. Nanophase HA possess characteristic features that improve cytocompatibility (Wei & Ma 2004), and improves bone development (Irvine et al. 2002). Nanocomposite may be achieved by integrating HA nanoparticles in PLLA. This composite system increases protein adsorption and compressive modulus. A composite structure of HA nanoparticles and PLGA arouses cell propagation and osteogenic differentiation (Chris –Arts et al. 2006).

Diverse methods have been applied to combine nano-TCP and nano-HA including sol–gel fusion, mechanochemical fusion, wet chemistry, co-precipitation, and micro-emulsion fusion (Venugopal et al. 2008). One popular approach is the sol–gel method as it may enhance purity and decrease synthesis temperature when likened to other approaches. Introduction of nano-crystals to composites as bone graft replacements enhances bone cell function (Kim et al. 2006) In vivo research studies illustrate bone development in various nanocomposites and nanomaterials. Injectable artificial adhesive comprising unadulterated nano-sized HA crystals were grafted in the dorsal skinfold cavities in a Syrian golden hamster replica (Laschke et al. 2006).

Nano-materials in Australia’s Medical System

The use of nano-structures in bone reconstruction is widely accepted and currently under research in Australia. An on-going project focuses on fabricating multifunctional bio-materials using Mesoporous Bioactive Glasses (MBGs) that have exceptional bone-creating bioactivity, biodegradability, biocompatibility. Traditional methods for treating bones and orthopaedic illnesses are principally ineffectual and may result in notable side-effects. It is necessary to introduce new form of multifunctional treatment methods that may increase bone development and heal bone deficiencies. The estimated development in materials and bone repair methods will enable injectable treatment, increased drug administration volume, and regulated drug introduction, bone tissue manufacturing framework and bone-fill processes (Xiaoxia 2014).

The importance of nanostructures in medicine has resulted in an increase in research and project topics that focus on this field of medicine. This is evident in Australia with a significant amount of research projects currently focusing on the importance of nano-materials, not only in bone treatment, but in other aspects of medicine.

An Australian project focuses on the use of nanostructures to improve vaccination processes. The project focuses on contributing to the actualization of needle-free vaccination processes. The project was successfully accomplished by integrating the experiences and expertise of chemists, dermatologists, biomedical professionals, materials science professors, vaccinologists and immunologists.

An important accomplishment was the creation and verification of the success of the Nanopatch needle-free vaccine process, which led to the establishment of a dedicated company to promote the Nanopatch. In spite of the success of the Nanopatch, there are some significant issues that need to be addressed within the basic areas of the group. For instance, there is need to investigate the possible damages that may result from mechanically exposing the skin to the patch (Kendall 2014). Research must focus on developing the safest device for the nanostructure-based needle-free vaccination process.

The project will also focus on investigating the chemistry involved in the production of optimally safe Nanopatch vaccines. The project also concentrates on the immunology dynamics involved in the use of nanostructures for vaccine procedures (Kendall 2014). These investigations will focus on the basic immunological dynamics, in the local tissue location and at additional sites, as well as utilisation of the foundational dynamics for enhanced vaccination products. This research indicates Australia’s proactive approach for the discovery and propagation of nanostructure inclusion in medicine (Kendall 2014).

Another project focuses on investigating the use nanostructures for vaccination procedures. The research summarises the approaches used for nanostructure based vaccination. Inoculation is a one of the most advanced methods of public health management systems. As vaccine production gradually shifts towards subunit structure, based on current ideas of practical design and enhanced safety outline, new adjuvant designs and distribution processes are gradually required to enhance the immunogenicity of the simple vaccines.

The project focuses on integrating vaccine production processes with nano-engineering, advancing vaccine systems that distribute vaccines at an amount and swiftness that cannot be achieved with the presently accepted vaccine production methods. The system applies self-integrations of virus-related capsid nutrients that create a pentameric system, referred to as capsomere, as a distribution method to current antigenic units from target infections (Wibowo 2014). Possessing virus-related molecular characteristics, sectional capsomere catalyses possible immune responses that may be enhanced through nanoparticle enhanced production. The research focused on vaccine modelling, bioprocessing, and production.

The section of vaccine modelling focuses on the strategies and mechanical systems used in antigenic units (Wibowo 2014). Bioprocessing investigates protein expression, cleansing, and procedure optimisation, and detailed protein classification, from simple to complex protein conditions (Wibowo 2014). Vaccine production investigates the application of modern nanotechnology to produce viral nano-elements. The outcome of the project will motivate a vaccine technology that may quickly change the methods currently applied for fighting viral infections (Wibowo 2014).

Another research group goes beyond investigating the use of nanostructures for vaccination processes, and focuses on investigating the application of nanostructures for the development of pharmaceuticals. The project is motivated by the understanding of the value of complex pharmaceuticals designed for cancer and other fatal diseases. The value of such medications is a result of the investments required for research, and the complicated procedures necessary for production (Gray 2014).

While new drug objectives will constantly be classified via fundamental investigation, the production of these drugs will eventually turn out to be the major setback of the drug production process because if the drugs cannot be produced, they basically cannot be utilised. By understanding the need for effective drug production processes, the project focuses on connecting new platforms and strategies to facilitate the production of new drugs (Gray 2014).

The major strategy this project focuses on is the use of dedicated nanostructures for the production of life-saving medication, which includes protein synthesis and monoclonal antibodies to reduce the cost of production and increase the number of patients receiving the drugs (Gray 2014). Platform technology comprises of hereditary production of recombinant cells and transmission of the hereditary substances into animal cells for protein generation. The project also seeks to investigate the cleansing and classification of the medication, in planning for human or animal trials (Gray 2014).

Another research study investigates the mechanisms involved when nano-particles contribute to the regeneration of cancer cells. The studies focus on directed distribution of nano-substances transporting cytotoxic medications to cancerous cells (Mahler 2014). Other target cells and antibodies designed for the target cells are being investigated (Mahler 2014). This is achieved by the conjugation of antibody particles to nano-fragments through different chemical and technological methods (Mahler 2014).

The nano-fragments that are integrated with the antibodies are categorised by an integration of various approaches, such as plasmon external reverberation and fluorescence triggered cell categorization to reveal connection to targets, as well as a range of internal and external bioassays to indicate performance (Mahler 2014).

The use of nano-technology for the treating cardiac failures has also been investigated. The investigation focuses on the application of direct reprogramming as a treatment method for cardiac diseases. Progressions in the ability of scientists to transform somatic cells by reprogramming have resulted in a recent innovation with regards to reformation of fibroblast cells into cardiomyocytes (Cooper-White 2014). These notable findings offer considerable possibilities for future treatment of injured heart tissue after an AMI (Acute Myocardial Infarct).

Nevertheless, the actualization of this possibility is presently restricted by the present utilisation of distribution methods that cannot be clinically interpreted, and the inability to immediately screen hereditary materials for improved and effective instant reprogramming results (Cooper-White 2014). A current research in Australia will focus on managing the problem of non-interpretable clinical methods by developing customised, cell-specified delivery methods developed for clinical interpretation and application (Cooper-White 2014).

The numerous nanotechnology related research studies currently carried out in Australia’s medical research systems indicates Australia’s understanding and acceptability of nanotechnology as a means for improving medical success. This positions Australia, not only as a country that is ready for the future, but also as a country that will actively contribute to the future of medicine.

Conclusion

The medical field has also recorded considerable advancement in terms of technology. Scientific research studies seek new methods of providing improved healthcare to patients. Tissue regeneration is an area of medicine that has recorded tremendous technological development. This review focused on the use of nanomaterials for bone repair and regeneration.

Presently, clinical reconstruction and repair of bone injuries are realized using allografts and auto-grafts with low success. To avoid complexities related to present treatments, the design and advancement of biomaterial scaffolds to enhance bone restoration has been an aspect of interest in the past years. The necessities for a model biomaterial bone implant are suitable mechanical features, biocompatibility, regulated bio-resorbability, and bioactivity, which encourage bonding between the original tissue and the graft. Polymeric substances enable precise manipulation of properties including architecture, mechanical features, and rate of degradation changing configuration and remodelling method.

The properties may be used to design grafts with the necessary properties for specific uses. Polymer combinations preserve the flexibility of polymeric scaffolds and incorporate the features of other materials, which may increase bioactivity or mechanical properties. Bio-absorbable or Biodegradable polymers are investigated since their degradation feature indicates that tissues may be deposited in them, however this is a significant design principle for bone recreation, as the mechanical integrity must not be compromised.

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