A method for forming a three-dimensional, biocompatible, porous scaffold structure using a solid freeform fabrication technique (referred to herein as robocasting) that can be used as a medical implant into a living organism, such as a human or other mammal. Imaging technology and analysis is first used to determine the three-dimensional design required for the medical implant, such as a bone implant or graft, fashioned as a three-dimensional, biocompatible scaffold structure. The robocasting technique is used to either directly produce the three-dimensional, porous scaffold structure or to produce an over-sized three-dimensional, porous scaffold lattice which can be machined to produce the designed three-dimensional, porous scaffold structure for implantation.

DESCRIPTION OF SPECIFIC EMBODIMENTS

Hydroxyapatite (HA), Ca₁₀(PO₄)₆(OH)₂, is a calcium phosphate ceramic commonly used for bone tissue repair in non-load bearing applications. Because bone cannot restore itself if a critical size defect is present, a porous scaffold to which cells can attach and proliferate is needed to fill and reconstruct the defect. As cells infiltrate the scaffold and proliferate, the scaffold degrades, freeing more space for continued cell growth and tissue formation. Eventually, the scaffolds are partially resorbed and incorporated into adjacent and remodeled bone.

Bone defects caused by trauma or disease may require repair via surgical intervention. In surgery, defects are filled with natural or synthetic grafts to inhibit fibrous tissue formation and to promote the ingrowth of bone tissue into the defect. Bone ingrowth is encouraged by scaffolds which are fabricated from biocompatible, osteoconductive materials, such as calcium phosphates. Hydroxyapatite (HA), a calcium phosphate, is an attractive material for bone applications when used to fabricate scaffolds or to coat implants such as titanium hip stems. For example, the addition of HA coatings on titanium promotes bone formation over titanium alone.

In addition to implant material, the surface topography of an implant plays a critical role in the bone cell response in vitro and in vivo. Osteoblast proliferation and matrix production in vitro has been shown to be affected by the surface topography of titanium. When titanium hip stems are implanted in vivo, surface topography affects the attachment rate and strength of the bone-implant bond. Smooth surfaces of titanium induce fibrous tissue, whereas rough surfaces induce bone formation. The type of tissue formation affects both the regenerated tissue quality and the strength of the tissue-implant bond. The strength of tissue-implant bond plays a major role in the clinical success of the implant.

Surface topography is typically produced by line of sight methods, such as plasma spraying onto and grit blasting of titanium implants or by polishing of ceramics. These methods are not applicable for creating topography on all surfaces of scaffolds, especially the surfaces of pores at the center of scaffolds. In order to create surface topography on HA scaffolds, techniques such as the addition of polymer fugitive porogen microspheres which burn out during processing and controlled sintering can be utilized. These pores cause changes in surface topography and may thereby affect cell-surface interactions that in turn mediate cell attachment, proliferation, spreading, differentiation, and function.

In vivo degradation of HA occurs by dissolution in aqueous body fluids, resorption by osteoclasts and multinuclear cells, and phagocytosis of particles by macrophages. As HA scaffolds degrade, strength is progressively lost. For load bearing applications, ingrown bone tissue must provide compensating strength in order to support mechanical load at the site of implantation. Eventually, the remodeled bone bears more load as the scaffold is slowly resorbed. As bone heals, the mechanical properties of the scaffold should decrease commensurately to accommodate the increasing strength provided by the ingrown bone. Bone subjected to increased load remodels and strengthens to accommodate such load. The inverse applies for decreased loads. Because proper bone repair requires load-bearing during the healing period, the porous, degrading scaffold must deform similarly to healthy bone under a given load, i.e. the implant must have an elastic modulus similar to that of bone. Scaffolds that provide too much or too little support for the bone may actually discourage new cell growth and consequently lengthen the healing process. Ideal mechanical properties of any scaffold will vary depending on the clinical application because the elastic modulus of bone differs according to anatomical location.

Microporous scaffolds dissolve more quickly than non-microporous scaffolds. The difference in dissolution rate is attributed to the surface area to volume ratio of the scaffolds. These differences allow for the tailorability of scaffold mechanical properties. A combination of microporous and non-microporous scaffolds would produce a scaffold with mechanical properties that match the properties of natural bone more closely. Such scaffolds possessing regions with and without local porosity formed by porogens could be produced by a solid freeform fabrication technique referred to herein as robocasting because multiple materials can be deposited in the same sample. In addition, scaffold mechanical properties can be tailored using the robocasting technique by altering the pore size, shape, and alignment. Scaffolds containing regions with and without local porosity formed by porogens have the potential to for a wide variety of load-bearing applications because the elastic modulus of bone differs by anatomical location.

In the present invention, a three-dimensional, biocompatible, porous scaffold structure, with examples of such structures illustrated in FIG. 1, is formed using robocasting that can be used as a medical implant into a living organism, such as a human or other mammal. Depicted in FIG. 1 are structures that represent a face-centered cubic (FCC) geometry, a simple cubic (SC) geometry, a modified FCC geometry, and a non-periodic geometry with individual elements. As shown in the flow-chart of FIG. 2, imaging technology and analysis, using computer implemented software 11 that can include mass transport software and solid mechanics software, are first used to determine the three-dimensional design 10 required for the medical implant, such as a bone implant or graft, fashioned as a three-dimensional, biocompatible scaffold structure. The robocasting technique 20 (although other rapid prototyping methods can be used) is used to either directly produce the three-dimensional, porous scaffold structure or to produce an over-sized three-dimensional, porous scaffold lattice which can be machined to produce the designed three-dimensional, porous scaffold structure for implantation.

One important feature of using the robocasting technique is the capability to produce controllable porosity on multiple scale levels, resulting in a scaffold structure with macroporosity (spacings ranging from greater than 50 microns to more than 1000 microns), microporosity (pore size diameters ranging from approximately 1 to 50 microns) and nanoporosity (comprising the porosity between grain boundaries of the materials used with diameters less than 1.0 microns). By controlling the material used, the pore structure and the sizes of the individual elements used to construct the three-dimensional scaffold structure, the strength of the scaffold structure can also be controlled, with compressive modulus values of greater than 5 GPa and compressive strength values from approximately 25 MPa to greater than 300 MPa achievable. The mechanical properties of the scaffold can thus be matched to the properties required of the implant; for example, the properties of a bone graft for a cortical bone (compressive modulus of 7-27 GPa and compressive strength of 85-224 MPa) can thus be matched.

Robocasting is a moldless-fabrication, rapid-prototyping technique, generally automated, for extruding concentrated particulate pastes, described by Cesarano III et al., (U.S. Pat. No. 6,027,326; incorporated by reference herein). The technique can be used in the formation of three-dimensional structures, including self-supporting lattice structures, from materials in a variety of shapes. Materials that can be used include, but are not limited to, ceramics, such as alumina, mullite, zirconia, silicon carbide, silicon nitride, zinc oxide, barium titanate, barium strontium titanate, lead zirconate titanate (PZT), kaolin, hydroxyapatite, hexaaluminates; metals, such as tungsten, silver, molybdenum, and stainless steel; polymers, thick-film pastes, epoxies, sol-gel materials, and composites, such as Al₂O₃/TiCuSil, Al₂O₃/Al, Al₂O₃/Mo, zirconia/mullite, porous/dense PZT materials, porous/dense alumina, and PZT/polymer materials.

In the robocasting process, highly concentrated slurries (suspensions) containing a powder (from a ceramic, metal, glass, polymer or composite material), with particle sizes generally around 1 micron in diameter, and solvent (generally water) are deposited, or 'written' in a layer-wise fashion with discrete or individual elements, with the process generally automated and computer controlled. The process is conceptually similar to icing a cake, with two-dimensional layers of the suspension material being sequentially deposited, and then writing subsequent layers in a rapid fashion to produce three-dimensional objects of high complexity. The highly concentrated suspensions generally contain very low amounts of organic material, allowing for prompt curing and final sintering of the part in a rapid-prototyping manner. Modifications to the robocasting process have shown that the technique can also be employed in a rapid-manufacturing environment. Controlling the viscous behavior of the suspension to a paste-like consistency enables shape retention of the deposited lines (in the form of cylindrical rods or other geometric shapes) of material until drying has taken place and also allows distances to be spanned. Proper adjustment of the ceramic suspension viscosity allows for the creation of self-supporting lattices or scaffolds. The mechanical properties of the scaffold structure can be tailored based on the physical and compositional characteristics of the individual shape elements and the geometry of those elements. Additionally, tortuosity and porosity of fluid flow paths can be tailored, based on design requirements, from straight-through pathways found in traditional honeycomb extrudates to pathways with no direct line-of-sight. These characteristics can prove important in enhancing cell growth in some situations. The geometry of the three-dimensional structure itself can also be controlled.

Examples of various three-dimensional frameworks or structures that can serve as the geometry of the scaffold structure, utilizing a sequence of cylindrical geometric constructs, are shown in FIG. 1. Depicted are structures that represent a face-centered cubic (FCC) geometry, a simple cubic (SC) geometry, a modified FCC geometry, and a non-periodic geometry with individual elements (in this case, cylindrical constructs, although other polyhedral geometrical constructs can be used, including those with rectangular, rhombic, trapezoidal, triangular or variable cross-sectional geometries,) comprising the three-dimensional structure of variable dimensions (diameters). The placement of these cylindrical constructs (rods) can be tailored to control both mechanical and fluid flow properties, based on design requirements. Sizes of the discrete elements used in the structure can vary within the structure but generally have characteristic dimensions ranging from approximately 0.05 mm to greater than 3 mm. For medical applications, the structures generally have sizes ranging from approximately 1 mm to greater than 200 mm, although larger structures can be fabricated if the application warrants.

In one example, a situation existed where it was desirable to fabricate and insert a scaffold structure into a severely deteriorated mandible. Imaging analysis was performed by taking a computerized axial tomographic (CAT) scan of the mandible area and using software to determine the three-dimensional geometry needed for a synthetic bone implant. Software was used to design a solid computer model of the implant. Robocasting was used to fabricate a three-dimensional, porous lattice structure comprising hydroxyapatite with size dimensions exceeding that of the desired bone implant. The fabricated lattice structure had a modified FCC structure using cylindrical rod elements with a macroporosity of approximately 50% based on the volume of the three-dimensional structure (with individual elements having spacings of 300-500 μm), a microporosity (based on the total volume of the individual elements) of approximately 30% (with pore sizes of approximately 6-10 μm), and a nanoporosity (based on the total volume of the individual elements) of approximately 10% (with pore sizes of approximately 0.5 μm). Using other geometries and materials, the macroporosity can range from 0-80%, the microporosity can range from 0-70%, and the nanoporosity can range from 0-60% (again, with the porosity of the latter two based on the volume of the individual elements) The fabricated structure had a compressive modulus of approximately 3.3 GPa and a compressive strength of approximately 137 MPa. The fabricated structure was machined using standard techniques to match the computer-developed solid model of the bone implant. The bone implant was then implanted into the deteriorated mandible using standard medical implant techniques.

Three-dimensional, porous biocompatible structures can also be fabricated according to the method of the present invention for the primary purpose of controlled drug dispersal within the living organism. Because the method of the present invention allows controlled tailoring of the pore structure of the implant on the macropore, micropore, and nanopore level, permitting control of fluid flow characteristics, implants can be fabricated that incorporate bioactive agents. There are essentially no limitations on the bioactive agents that can be incorporated into an implant using the method of the present invention, as the bioactive materials can either be incorporated directly into the slurry that forms the three-dimensional, porous structure or can be dispersed within the porosity of the three-dimensional porous structure. In the latter case, the bioactive agent can be contained within the porous structure either through physical or chemical means.

Examples of bioactive agents that can be used include growth factors, other proteins and peptides, nucleic acids, polysaccharides, nucleic acids, lipids, and non-protein organic and inorganic compounds. These bioactive agents can have biological effects including, but not limited to, anti-inflammatories, antimicrobials, anti-cancer, antivirals, hormones, antioxidants, channel blockers, and vaccines. It is also possible to incorporate materials not exerting biological effects such as radiopaque materials and other imaging agents.

When these bioactive agents are incorporated into the porosity of the structure and implanted into the living agent, they can be released into the agent either through mass transport through the structure or can be released as the structure erodes. The release rate can thus be controlled through proper design of the porous structure and a priori analysis of the transport properties of the bioactive agent and the erosion properties of the structure. Concentration variations of the bioactive agent can be intentionally incorporated into the implanted structure. Additionally, variations in erosion properties can be incorporated into the structure through control of material properties as well as geometric properties of the structure.
 

Claim 1 of 17 Claims

1. A method for making a three-dimensional, bio-compatible scaffold structure, comprising:

designing a three-dimensional geometry of a scaffolding structure utilizing software implemented by a computer;

said software selected from the group consisting of mass transport software and solid mechanics software to match a pre-selected property, said property selected from the group consisting of compressive modulus, compressive strength, porosity of the porous structure, tortuosity of the porous structure, and mass transport characteristics of the porous structure; and

depositing a bio-compatible slurry as discrete elements in said three-dimensional geometry using a robocasting rapid-prototyping method to construct a three-dimensional, porous structure, said three-dimensional porous structure comprising macroporosity between approximately 0 and 80%, microporosity of said discrete elements between 0 and 70% and nanoporosity of said discrete elements between approximately 0 and 60%.
 

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