Novel strategy for mechanically tunable and bioactive metal implants
Introduction
Metallic biomaterials have been widely used as load-bearing implants and internal fixation devices such as orthopedic, dental implants, and even vascular/non-vascular stents depending on design because of their excellent mechanical strength and resilience [1], [2], [3]. Despite the progress in load-bearing metal implant research, fixation of implants to the host tissue remains a problem. The mismatch between the elastic modulus of the implant material and that of the bone is the main reason that causes the stress to be shielded from reaching the bone in addition to low bioactivity of metallic materials that often leads to poor interface between the implant and biological tissues [4], [5], [6]. To overcome these problems, porous structures are being extensively investigated, since a reduction in elastic modulus can be coupled with bone integration through tissue ingrowth into pores to promote healthy recovery [7], [8], [9]. Various porous metals such as NiTi, titanium and tantalum have been proved to exhibit strong bone-implant contact and excellent bone ingrowth without signs of loosening from the surgical sites [8], [10], [11]. Moreover, recent studies have proposed various surface modification methods of metallic surface in order to improve biological activities, e.g., coating the metal surface with bioactive molecules (e.g., growth factors) or drugs (e.g., vancomycin, tetracycline) [12], [13], [14]. As compared to bare metals, the bioactive coating layer on a metal surface with or without drugs has shown accelerated healing processes of the implanted region or suppressed undesirable reactions between surrounding tissues and the implant [12], [15], [16]. These include titanium (Ti) ring implant with recombinant human bone morphogenetic protein (rhBMP-2), e.g., Ti alloy conjugated with synthetic peptide, and Ti screw coated with rhBMP-2 [17], [18], [19].
However, introduction of pores to metals has been found to come up with a tradeoff in the mechanical properties besides the reduction of stiffness. Although a porous structure facilitates bone ingrowth, uncontrolled or undesirable pores often result in significant decreases of the mechanical properties due to inherent structural instability associated with irregular, inhomogeneous pore structures and defects [20], [21]. Moreover, chemical contamination during the fabrication of porous metals has been found to cause embrittlement of the materials with decreased compressive strength [22], [23], [24]. Therefore, development in a fabrication method of porous metals that is able to provide mechanical tunability of a porous scaffold associated with various porosity features (e.g., pore fraction, shape, size, distribution, connectivity and gradient) and material properties (e.g., metallic phase and impurity) has been one of key challenges in order to achieve a balance between biological performance and mechanical stability [10], [25].
On the other hand, sustainable release of coating layers on metallic surface has been regarded as an issue of surface modification. Porous metallic implants have been considered as better drug carrier candidates as compared to dense metals because of large surface area. However, porous materials coated with substances experience burst effects in physiological environments, thus methods to control the rate of release is under much research. For example, in attempts to control the initial burst and to sustain the release of substances, nanopores are formed on the surface of implants or polymers with a low degradation rate is used to coat the implants [13], [26], [27], [28]. However, there are still some room for improvement such as controlling the side-effects caused by the coated polymers, reducing the additional processes needed to form nanopores, and fabricating uniform pore structures [29], [30], [31].
In this study, we have proposed densified porous Ti scaffolds as a drug carrier as well as load-bearing implants. The large surface area of the porous scaffolds is capable of loading significantly increased amount of drugs on the metal surface as compared to dense metal body of the same weight [32], [33]. In addition, microstructural modification associated with porosity and pore structures of the scaffolds provides mechanical tunability as well as controllable drug release behavior. To demonstrate the potential of porous scaffolds as a drug-loaded metal implant, we have coated porous titanium (Ti) scaffolds with one of well-known bone growth factors, BMP-2. BMP-2 is known to accelerate bone regeneration in the body so it has been widely applied in treatment of bone defects, and also as bioactive coating agents for orthopedic and dental implants [32], [34], [35]. However, negative side effects including heterotopic bone formation, retrograde ejaculation and osteoclast activation have also been reported with supraphysiologic doses of rhBMP-2 over relatively short periods [31], [36], [37], [38]. Therefore, many studies have tried to develop a carrier system which is capable of sustained and controlled release of rhBMP-2 over a prolonged period with the bioactivity of the growth factor still maintained [39], [40], [41]. Here, we have fabricated porous Ti scaffolds through a dynamic freeze casting process, and coated the scaffolds with rhBMP-2 varying the amount of rhBMP-2 loading with initial porosity. Through densification of the porous scaffolds, modified porosity and pore structures were evaluated in terms of mechanical properties as well as drug release behavior. Moreover, herein, we report for the first time in vitro rhBMP-2 release studies for a prolonged period in parallel to in vivo study in order to prove biological improvement of rhBMP-2-coated Ti samples.
Section snippets
Fabrication of densified porous titanium coated with biomolecules
The schematic of sample preparation was illustrated in Fig. 1. In this study, porous Ti scaffold coated with rhBMP-2, a bone growth factor, was studied as a model system for orthopedic applications. Porous Ti scaffolds were fabricated by dynamic freeze casting [42], which enables production of mechanically stable metal scaffolds with 3-dimensionally interconnected porous channels. All samples were sterilized in an autoclave for 15 min at 121 °C. Following the sterilization, the scaffolds were
Densification of Ti scaffolds
The porosity of Ti samples was controlled by the degree of densification associated with the applied strain (εzz) as shown in Fig. 2a. Cylindrical samples with three initial porosities (I.P.) of 50%, 60% and 70% were applied with uniaxial pressure within a mold that constrained radial deformation and only allowed the z-axis deformation. The optical image of the sample is shown in terms of degree of densification corresponding to the height of each sample. The heights of the sample decreased as
Discussion
Even though biometals have been widely used for biomedical applications, there is still room for improvement because of mechanical mismatch and low bioactivity. In particular, recent studies that focus on the surface modification of grafting materials for inducing rapid bone ingrowth have utilized stimulatory molecules, which includes peptides, proteins, and growth factors on the surface that enables quicker and more stable cell colonization [45], [46]. Considerable effort has been devoted to
Conclusions
Densified porous titanium was successfully fabricated, where the degree of densification was controlled by the applied strain under uniaxial compression. During densification, structural integrity of porous titanium was well maintained without any mechanical deterioration under various cyclic loading conditions, exhibiting good pore connectivity and large surface area. Densified porous titanium possesses two important features that have not been achieved by either dense titanium or porous
Acknowledgments
This research was supported by the Technology Innovation Program (Contract grant No. 0037915, WPM Biomedical Materials—Implant Materials) funded by the Ministry of Knowledge Economy (MKE, Korea). Also, L.F. Wang acknowledges the support of the National Science Foundation (CMMI-1437449).
References (81)
- et al.
Titanium alloys in total joint replacement-a materials science perspective
Biomaterials
(1998) - et al.
Production and evaluation of porous titanium scaffolds with 3-dimensional periodic macrochannels coated with microporous TiO2 layer
Mater Chem and Phys
(2012) - et al.
Assessment of bone ingrowth into porous biomaterials using MICRO-CT
Biomaterials
(2007) - et al.
Bone ingrowth in porous titanium implants produced by 3D fiber deposition
Biomaterials
(2007) - et al.
Production of highly porous titanium (Ti) scaffolds by vacuum-assisted foaming of titanium hydride (TiH2) suspension
Mater Lett
(2014) - et al.
The effect of pretreating morselized allograft bone with rhBMP-2 and/or pamidronate on the fixation of porous Ti and HA-coated implants
Biomaterials
(2008) - et al.
Implanting hydroxyapatite-coated porous titanium with bone morphogenetic protein-2 and hyaluronic acid into distal femoral metaphysis of rabbits
Chin J Traumatol (English Edition)
(2008) - et al.
Growth factor-loaded scaffolds for bone engineering
J Control Release
(2005) - et al.
The influence of recombinant human BMP-2 on bone–implant osseointegration: biomechanical testing and histomorphometric analysis
Int J Oral Maxillofac Surg
(2007) - et al.
Growth of new bone guided by implants in a murine calvarial model
Bone
(2008)
Compressive and pseudo-elastic hysteresis behavior of entangled titanium wire materials
Mater Sci Eng A
Mechanical behavior of porous magnesium/alumina composites with high strength and low density
Mater Sci Eng A
Improving the strength and biocompatibility of porous titanium scaffolds by creating elongated pores coated with a bioactive, nanoporous TiO2 layer
Mater Lett
Mechanical properties of directionally freeze-cast titanium foams
Acta Mater
Fabrication of porous titanium scaffold with controlled porous structure and net-shape using magnesium as spacer
Mater Sci Eng C.
Cytocompatibility and mechanical properties of novel porous 316L stainless steel
Mater Sci Eng C
Basic fibroblast growth factor suspended in Matrigel improves titanium implant fixation in ovariectomized rats
J Control Release
Biomimetic modification of the TiO2/glass composite Ecopore with heparinized collagen and the osteoinductive factor BMP-2
Acta Biomater
Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2)
Spine J
Retrograde ejaculation after anterior lumbar interbody fusion using rhBMP-2: a cohort controlled study
Spine J
Resorbable synthetic polymers s replacements for bone graft
Clin Mater
Biomaterial developments for bone tissue engineering
Biomaterials
Enhanced osteoinduction by controlled release of bone morphogenetic protein-2 from biodegradable sponge composed of gelatin and β-tricalcium phosphate
Biomaterials
Dynamic freeze casting for the production of porous titanium (Ti) scaffolds
Mater Sci Eng C.
Effects of biomimetically and electrochemically deposited nano-hydroxyapatite coatings on osseointegration of porous titanium implants
Oral Surg Oral Med Oral Pathol, Oral Radiol, Endodontol
Osteointegration of hydroxyapatite-titanium implants coated with nonglycosylated recombinant human bone morphogenetic protein-2 (BMP-2) in aged sheep
Bone
Printing of Titanium implant prototype
Mater Des
Scaffolds in tissue engineering bone and cartilage
Biomaterials
Fabrication methods of porous metals for use in orthopaedic applications
Biomaterials
Low stiffness porous Ti structures for load-bearing implants
Acta Biomater
Effects of solid distribution on the stiffness and strength of metallic foams
Acta Mater
Biomechanics of cellular solids
J Biomech
Biomaterials in total joint replacement
Colloids Surfaces B Biointerfaces
Magnesium and its alloys as orthopedic biomaterials: a review
Biomaterials
Numerical modeling of pore size and distribution in foamed titanium
Mech Mater
Controlled release of bone morphogenetic protein (BMP)-2 from nanocomplex incorporated on hydroxyapatite-formed titanium surface
J Control Release
Strategies for controlled delivery of growth factors and cells for bone regeneration
Adv Drug Deliv Rev
Catechol-functionalized adhesive polymer nanoparticles for controlled local release of bone morphogenetic protein-2 from titanium surface
J Control Release
Mechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices
J Pharm Sci
Rate of release of medicaments from ointment bases containing drugs in suspension
J Pharm Sci
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