Matthew Wettergreen

Creation of a unit block library of architectures for use in assembled scaffold engineering

Guided tissue regeneration is gaining importance in the field of orthopaedic tissue engineering as need and technology permits the development of site-specific engineering approaches. Computer Aided Design (CAD) and Finite Element Analysis (FEA) hybridized with manufacturing techniques such as Solid Freeform Fabrication (SFF), is hypothesized to allow for virtual design, characterization, and production of scaffolds optimized for tissue replacement. However, a design scope this broad is not often realized due to limitations in preparing scaffolds both for biological functionality and mechanical longevity. To aid scientists in fabrication of a successful scaffold, we propose characterization and documentation of a library of micro-architectures, capable of being seamlessly merged according to the mechanical properties (stiffness, strength), flow perfusion characteristics, and porosity, determined by the scientist based on application and anatomic location. The methodology is discussed in the sphere of bone regeneration, and examples of catalogued shapes are presented. Similar principles may apply for other organs as well.

Computer-Aided Tissue Engineering of a Human Vertebral Body

Tissue engineering is developing into a less speculative science involving the careful interplay of numerous design parameters and multidisciplinary professionals. Problem solving abilities and state of the art research tools are required to develop solutions for a wide variety of clinical issues. One area of particular interest is orthopedic biomechanics, a field that is responsible for the treatment of over 700,000 vertebral fractures in the United States alone last year. Engineers are currently lacking the technology and knowledge required to govern the subsistence of cells in vivo, let alone the knowledge to create a functional tissue replacement for a whole organ. Despite this, advances in computer-aided tissue engineering are continually growing. Using a combinatory approach to scaffold design, patient-specific implants may be constructed. Computer-aided design, optimization of geometry using voxel finite element models or other optimization routines, creation of a library of architectures with specific material properties, rapid prototyping, and determination of a defect site using imaging modalities highlight the current availability of design resources. This study proposes a novel methodology from start to finish which could, in the future, be used to design a tissue-engineered construct for the replacement of an entire vertebral body.

Computer-Aided Tissue Engineering: Benefiting from the Control Over Scaffold Micro-Architecture

Minimization schema in nature affects the material arrangements of most objects, independent of scale. The field of cellular solids has focused on the generalization of these natural architectures (bone, wood, coral, cork, honeycombs) for material improvement and elucidation into natural growth mechanisms. We applied this approach for the comparison of a set of complex three-dimensional (3D) architectures containing the same material volume but dissimilar architectural arrangements. Ball and stick representations of these architectures at varied material volumes were characterized according to geometric properties, such as beam length, beam diameter, surface area, space filling efficiency, and pore volume. Modulus, deformation properties, and stress distributions as contributed solely by architectural arrangements was revealed through finite element simulations. We demonstrated that while density is the greatest factor in controlling modulus, optimal material arrangement could result in equal modulus values even with volumetric discrepancies of up to 10%. We showed that at low porosities, loss of architectural complexity allows these architectures to be modeled as closed celled solids. At these lower porosities, the smaller pores do not greatly contribute to the overall modulus of the architectures and that a stress backbone is responsible for the modulus. Our results further indicated that when considering a deposition-based growth pattern, such as occurs in nature, surface area plays a large role in the resulting strength of these architectures, specifically for systems like bone. This completed study represents the first step towards the development of mathematical algorithms to describe the mechanical properties of regular and symmetric architectures used for tissue regenerative applications. The eventual goal is to create logical set of rules that can explain the structural properties of an architecture based solely upon its geometry. The information could then be used in an automatic fashion to generate patient-specific scaffolds for the treatment of tissue defects.

Scaffold Pore Space Modulation Through Intelligent Design of Dissolvable Microparticles

The goal of this area of research is to manipulate the pore space of scaffolds through the application of an intelligent design concept on dissolvable microparticles. To accomplish this goal, we developed an efficient and repeatable process for fabrication of microparticles from multiple materials using a combination of rapid prototyping (RP) and soft lithography. Phase changed 3D printing was used to create masters for PDMS molds. A photocrosslinkable polymer was then delivered into these molds to make geometrically complex 3D microparticles. This repeatable process has demonstrated to generate the objects with greater than 95% repeatability with complete pattern transfer. This process was illustrated for three different shapes of various complexities. The shapes were based on the extrusion of 2D shapes. This may allow simplification of the fabrication process in the future combined with a direct transfer of the findings. Altering the shapes of particles used for porous scaffold fabrication will allow for tailoring of the pore shapes, and therefore their biological function within a porous tissue engineering scaffold. Through permeation experiments, we have shown that the pore geometry may alter the permeability coefficient of scaffolds while influencing mechanical properties to a lesser extent. By selecting different porogen shapes, the nutrition transport and scaffold degradation can be significantly influenced with minimal effect on the mechanical integrity of the construct. In addition, the different shapes may allow a control of drug release by modifying their surface-to-volume ratio, which could modulate drug delivery over time. While soft lithography is currently used with photolithography, its high precision is offset by high cost of production. The employment of RP to a specific resolution offers a much less expensive alternative with increased throughput due to the speed of current RP systems.

Unit Block Library of Basic Architectures for Use in Computer-Aided Tissue Engineering of Bone Replacement Scaffolds

Guided tissue regeneration focuses on the implantation of a scaffold architecture, which acts as a conduit for stimulated tissue growth. Successful scaffolds must fulfill three basic requirements: provide architecture conducive to cell attachment, support adequate fluid perfusion, and provide mechanical stability during healing and degradation. The first two of these concerns have been addressed successfully with standard scaffold fabrication techniques. In instances where load bearing implants are required, such as in treatment of the spine and long bones, application of these normal design criteria is not always feasible. The scaffold may support tissue invasion and fluid perfusion but with insufficient mechanical stability, likely collapsing after implantation as a result of the contradictory nature of the design factors involved. Addressing mechanical stability of a resorbable implant requires specific control over the scaffold design. With design and manufacturing advancements, such as rapid prototyping and other fabrication methods, research has shifted towards the optimization of scaffolds with both global mechanical properties matching native tissue, and micro-structural dimensions tailored to a site-specific defect. While previous research has demonstrated the ability to create architectures of repetitious microstructures and characterize them, the ideal implant is one that would readily be assembled in series or parallel, each location corresponding to specific mechanical and perfusion properties. The goal of this study was to design a library of implantable micro-structures (unit blocks) which may be combined piecewise, and seamlessly integrated, according to their mechanical function. Once a library of micro-structures is created, a material may be selected through interpolation to obtain the desired mechanical properties and porosity. Our study incorporated a linear, isotropic, finite element analysis on a series of various micro-structures to determine their material properties over a wide range of porosities. Furthermore, an analysis of the stress profile throughout the unit blocks was conducted to investigate the effect of the spatial distribution of the building material. Computer Aided Design (CAD) and Finite Element Analysis (FEA) hybridized with manufacturing techniques such as Solid Freeform Fabrication (SFF), is hypothesized to allow for virtual design, characterization, and production of scaffolds optimized for tissue replacement. This procedure will allow a tissue engineering approach to focus solely on the role of architectural selection by combining symmetric scaffold micro-structures in an anti-symmetric or anisotropic manner as needed. The methodology is discussed in the sphere of bone regeneration, and examples of cataloged shapes are presented. Similar principles may apply for other organs as well.Copyright

Surface-Based Scaffold Design: A Mechanobiological Approach

Despite recent need-based advances in orthopedic scaffold design, current implants are unsuitable as “total” scaffold replacements. Both mechanical requirements of stiffness/strength and biological stipulations dictating cellular behavior (attachment, differentiation) should be included. The amount of mechanical stimulation in the form of stresses, strains, and energies most suitable toward implant design is presently unknown. Additionally unknown is if whole-bone optimization goals such as uniform and non-uniform driving forces are applicable to a scaffold-bone interface. At the very least, scaffolds ready for implantation should exhibit mechanical distributions (dependent on loading type) on the surface within the typical mechanical usage window. Scaffold micro-architectures can be strategically shifted into that window. The overall goal of this study was to produce microarchitectures tailored to a more uniform mechanical distribution, while maintaining the morphological properties necessary to sustain its mechanical integrity. The mechanical adjustment stimuli investigated were von Mises stress, strain energy density, maximum principle strain, and volumetric strain. Scaffold models of a similar volume fraction were generated of three initial architectures (Rhombitruncated Cuboctahedron, hollow sphere, and trabecular-like bone cube) using high resolution voxel mapping. The resulting voxels were translated into finite element meshes and solved, with a specially written iterative solver created in Fortran90, under confined displacement boundary conditions. The result was verified against a commercial software. Once the mechanical distributions were identified one of two methods was chosen to alter the configuration of material in Cartesian space. The success of the alteration was judged through a diagnostic based on the histogram of mechanical values present on the surface of the micro-architecture. The first method used a compliant approach and, for the case of stress, reinforced locations on the surface with large stresses with extra material (strategically taken from the least stressed portions). The second method used a simulated annealing approach to randomly mutate the initial state in a “temperature” dependent manner. Results indicate that the mechanical distributions of the initial scaffold designs vary significantly. Additionally, the end state of the adjustment demonstrated anisotropy shifts toward the direction of loading. Moreover, the adjustment methods were found to be sensitive both to the mechanical parameter used for adjustment and the portion of the surface adjusted at each increment. In conclusion, scaffolds may be adjusted using a mechanical surface-based objective, as the surface of the scaffold is crucial toward its in vivo acceptance. This technique provides some mathematical specificity toward the whole of computer-aided tissue engineering.Copyright