Biomedical Applications of Metal Additive Manufacturing: Current State-of-the-Art and Future Perspective

Recent developments in Additive Manufacturing (AM) have provided unprecedented opportunities for emerging metal implant technologies. These technologies can combine unique architectures tailored to patient-specific needs, and potentially absorbable properties that could aid in the healing process. Advanced imaging techniques enable the reconstruction of the affected regions and the design of the implant, while AM can be used to print the patient-specific implant. Metallic metamaterials have been fabricated based on designed lattice structures with precisely controlled porous structures having specific functional and mechanical properties for the desired application. This review summarizes the current state-of-the-art and future opportunities for metal AM in biomedical applications.


Introduction
In the last decade, advancements in metal Additive Manufacturing (AM) have revolutionized the biomedical field by providing an innovative asset for the development of new clinical technologies (e.g. guides for surgical procedures, scaffolds for tissue engineering, and load bearing implants) [1][2][3][4][5][6]. The majority of metal AM technologies rely on the continuous fusion of a metallic feedstock (powder, wire or sheets) using a high energy source (laser, electron beam or plasma) in a layer-by-layer fashion to manufacture structures based on a user-defined computer aided design (CAD) model [4,7]. Based on its intrinsic layer-by-layer operation, AM allows the fabrication of structures with complex geometries that cannot be achieved by conventional subtractive methods [2,3,8].
The ease of design customization and the achievable structural complexity via AM could present a new solution to unanswered challenges in orthopedics [2][3][4][8][9][10]. These challenges include the inability for current metallic implants to mimic the structure and mechanical properties of the bone, which in turn can compromise the fixation of orthopedic implants, inaccurate anatomical fitting that adversely affect surgical placement of the devices, and limited restoration of the biological function of the remaining bone surrounding the implant [11][12][13][14].
This review focuses on the advantages and significant contributions of AM to modern orthopedics. The fabrication of metallic metamaterials with osteoconductive properties and tailored mechanical/functional responses to cater to patientspecific needs are discussed. Moreover, the prospect to develop novel absorbable implants using alloys of biodegradable metals is also reviewed.

Recent Advances in AM for Orthopedic Implants Topology optimization
Topology Optimization is a promising tool to discover novel architectures with desirable structural and functional properties.
This optimization method seeks to determine the optimal material distribution that will fulfils a set of pre-defined boundary conditions [26][27][28]. The optimized structures usually have complex geometries that are difficult to manufacture using conventional methods but can be produced owing to the geometric freedom offered by AM.
Topology optimization is a promising route to discover novel architectures with desirable structural and functional properties [27,29,30].
In addition to optimizing based on mechanical constraints, topology optimization can integrate fluidic boundary conditions that will account for the required permeability for tissue ingrowth maximizing cell migration and mass transport [30,31]. This aspect of topology optimization has been used outside of orthopedics, in developing efficient metallic stents for treating aneurisms, and in making scaffolds for regeneration of tissues [32,33].

Meta-implants
The mechanical properties of conventional materials are primarily dictated by their chemical composition and their microstructure. Mechanical metamaterials challenge these conventional material definitions by engineering structures that exhibit counter-intuitive mechanical properties (e.g. materials that display remarkably low stiffness or a zero or negative Poisson's ratio). Metamaterials are often characterized by having ordered cellular lattices relating their density to their mechanical response and functionality and thus allowing them to be controlled. In the fabrication of orthopedic implants, metamaterials can provide structures with gradient porosities and stiffness similar to the intricate structure of bone in which cortical bone with high modulus (13.6GPa-28GPa) morphs regionally into low modulus cancellous bone (0.02GPa-0.64GPa) [34].
Complex metamaterial structures could serve to improve the interactions at the bone-implant interface and exhibit osteoconductive properties providing an optimized environment for tissue integration [10,35]. Meta-implants manufactured using tetrahedral unit cells and customized gradient densities have shown potential in reducing bone-loss resulting from stress shielding by ~75% [36]. Orthopedic implants often incorporate intramedullary stems for fixation to the endosteal surfaces of long bones like the femur and humerus. The resulting implant bone composite is constantly subjected to bending and torsional loads, often leading to failure of the bone-implant interface. Moreover debris (caused by fretting wear) can get trapped at the interface causing osteolysis [37].
The design of implants combining auxetic and non-auxetic metamaterials on the interfaces subject to tensile and compressive loading respectively, have shown the ability to eliminate the retraction of the implant from the bone by inducing expansion at both interfaces, even as the material undergoes tensile loading [38].
This can result in increased implant longevity and reduced need for revision surgery.

Patient-specific implants
Despite the widespread availability of implant systems with several sizes to fit a broad spectrum of anatomy, cases nonetheless arise in which a standard commercial device will not suffice. This information can be used to help design not just the shape of the implant, but it's local structural and mechanical properties.
In this way load transfer between the implant and the surrounding remnant bone can be optimized to assure both short-term fixation and longevity [39,40]. The direct reconstruction of anatomical regions via CT images has been effectively implemented for the accurate design of orbital socket [41], hip [42], and sternal implants [12] manufactured via AM techniques. The surgical procedures with sternal implants demonstrated immediate structural support and significant improvement in patients' respiratory symptoms post-operatively [12].

Absorbable metallic implants
Titanium alloys [43], cobalt-chromium alloys [44], tantalum and stainless steel [45,46] are metallic materials commonly used in permanent orthopedic implants due to their high structural integrity, corrosion resistance and biocompatibility. However, Moreover, in pediatric patients, metal implants must often be removed to allow bone growth as the child gets older. The process of removing the implant requires another surgery, which comes with an additional risk of surgical complications, pain and rehabilitation and of course, additional financial burden.

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Although, polymers have long been used to make resorbable implants, they do not meet the structural requirements needed in plates, screws or most load bearing implants. In addition, degradation of synthetic polymer-based resorbable structures have shown to result in inflammation and the formation of 'sterile' abscesses [47]. Magnesium, iron and zinc are metals with bioresorbable properties and are essential trace metals in normal human physiology [48]. Using alloys of these metals, implants can be manufactured with AM to have tuneable degradation rates that match the rate of bone formation for the given application reducing the risk of infection and cytotoxicity [49,50]. Further, these implants could release metal ions in non-toxic quantities that may even be beneficial to the healing process [51].