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    • 专利摘要:
    additive manufacturing of continuous digital light processing implants. The present invention relates to the additive embodiment of a resorbable implant to be implanted in a patient which includes providing a resin that includes a liquid light polymerizable material that is resorbable after polymerization and an initiator. the process further includes driving an additive manufacturing apparatus to expose a resin amount to light to at least partially cure the exposed amount of resin to form a resorbable implant layer and triggering the additive manufacturing apparatus to expose some additional amount of resin to light to at least partially cure the additional exposed amount of resin to reshape an additional layer of resorbable implant and at least partially over cure the previously cured layers to cause at least some intermediate layer bonding between the previously cured layers and the additional layer.
    公开号:BR112013003863B1
    申请号:R112013003863-2
    申请日:2011-08-22
    公开日:2018-07-10
    发明作者:David Dean H.；E. Wallace Jonathan；G. Mikos Antonios；Wang Martha；Siblani Ali；Kim Kyobum；P. Fisher John
    申请人:Case Western Reserve University；Envisiontec, Inc.；University Of Maryland；Rice University；
    IPC主号:
    专利说明:

    (54) Title: PROCESS OF MANUFACTURING A SUPPORT FOR TISSUE ENGINEERING, PROCESS FOR MANUFACTURING BY PROCESSING OF CONTINUOUS DIGITAL LIGHT OF AN IMPLANT, PROCESS FOR ADDITIVE MANUFACTURING OF A REABSIBLE AND IMPLANT IMPLANT (51) Int.CI .: A61L 27 / 14; G02B 26/00; A61L 27/56; A61L 27/54; A61L 27/40 (30) Unionist Priority: 8/20/2010 US 61 / 375,353, 5/29/2011 US 61 / 491,194 (73) Holder (s): CASE WESTERN RESERVE UNIVERSITY. ENVISIONTEC, INC .. UNIVERSITY OF MARYLAND. RICE UNIVERSITY (72) Inventor (s): H. DAVID DEAN; JONATHAN E. WALLACE; ANTONIOS G. MIKOS; MARTHA WANG; ALI SIBLANI; KYOBUM KIM; JOHN P. FISHER
    1/21 “PROCESS OF MANUFACTURING A SUPPORT FOR TISSUE ENGINEERING, PROCESS FOR MANUFACTURING BY PROCESSING OF CONTINUOUS DIGITAL LIGHT OF AN IMPLANT, PROCESS FOR ADDITIVE MANUFACTURING OF A REABSIBLE AND IMPLANT IMPLANT”
    Cross Reference to Related Orders
    This application claims the benefit of U.S. provisional patent applications numbers 61 / 373,353, filed on August 20, 2010 and 61 / 491,194, filed on May 29, 2011, which are incorporated by reference in this document.
    Federal Financing Information
    Portions of the subject matter claimed were developed with federal funding provided under NIH grant number R01-DE013740.
    Background of the Invention
    Implants can be designed to match a defect in a patient's tissue. The shape of the implant can be determined by first measuring the defective area or volume within the patient. The implant can then be designed, for example, computer aided design (CAD) due to the area or volume of the measured defect. The implant can then be manufactured.
    Factors that must be taken into account when designing and manufacturing implants include the appropriate geometry to provide an appropriate fit within the patient and, in the case of tissue engineering scaffolds, to facilitate the growth of host tissue and vascular infiltration.
    The functional geometric features of a support can be designed to affect cell adhesion, proliferation or maturation. Surface features that interact directly with cells include roughness and support porosity. The crude porous structures can facilitate cell loading, growth of new tissue and intracrescence of host tissue. The designer can manipulate the porous geometry to control both the mechanical properties of the entire implant, as well as the pore space porosity, tortuosity, permeability and total pore volume. Many tissue engineering supports may require pores ranging from 200 to 1600 gm with surface features, such as the shape of the pore opening, in the order of 50-500 gm. Conventionally, these resources may have been obtained, if possible, through the inclusion of particles, such as crystals of tricalcium phosphate in the resin from which the support can be manufactured. However, concerns may arise about the reabsorbability of the crystals in the host's body.
    Another important geometric feature may be the oblique orientation of pore structures so that the host tissue does not find a wall or barrier in the support, which is more likely when the pore structures are orthogonally constructed than when the
    2/21 pores or channels are oriented towards the host tissue. The creator of the implant may wish to orient the pore channels within a support, so that they open towards the host tissue, thus facilitating the growth of new tissue in the implant and the active incorporation of the implant into the host tissue.
    Additive manufacturing of implants or supports with these mechanical and geometric features requires relatively high levels of accuracy. For example, accurate rendering makes it more likely that complex internal pore structures, such as those described above and others, can be created.
    Additional factors to take into account when designing and manufacturing implants or supports are adequate strength and toughness for the part to handle and transmit mechanical stress. In some cases, resistance and hardness must be weighed against the need for the implant or support to be resorbable or able to decompose in the host's body. The manipulation of the molecular weight of the polymer often adjusts the levels of resorption versus the strength of the implant, with the higher molecular weights often being stronger and the lower molecular weights often being more absorbable. However, post-cure manipulation of low molecular weight supports or implants can be problematic and, therefore, the ideal rendering process can minimize any necessary post-cure manipulation.
    Although stereolithographic rendering of implants and supports has been demonstrated, limitations on commercially available devices result in relatively low levels of accuracy.
    For example, the accuracy and resolution of conventional stereolithographic rendering devices may not allow the devices to produce support or implant surface features, such as pores and pore openings at the low end of the optimal geometric scale. And while conventional stereolithographic rendering devices may be able to produce orthogonally oriented pore structures on implants and supports, they provide insufficient resolution to produce obliquely oriented pores.
    In addition, stereolithographic rendering may also have several other limitations in the context of the manufacture of implants or supports.
    For example, conventional stereolithographic devices use a laser to polymerize the layers. The laser points down at the top of a container of liquid polymer. An elevator sits inside the container and pulls the part down as it is rendered, layer by layer. Typically, the drawing speed is not fast enough to draw all the pixels on the layer simultaneously, which can make it difficult to control over-seam or stitching between the layers as the implant or support is produced.
    3/21
    Also, conventional stereolithographic devices may not provide a way to modulate the amount of energy at one point versus another within a layer to, for example, control the polymerization depth and level or overheat resistance.
    In addition, conventional stereolithographic devices may require the use of a cleaning blade to smooth the resin between each layer to provide a flat surface. Highly viscous polymers can present reliability problems for this planing tool.
    In addition, stereolithographic polymerization of resorbable polymer supports using low molecular weight polymers presents challenges. Conventional stereolithographic rendering devices often require post-rendering manipulation to complete healing of the support or implant, which can be very difficult and can result in distortion or destruction of the low molecular weight polymer support or implant.
    Brief Description of Drawings
    The attached drawings, which are incorporated and constitute a part of the specification, illustrate various systems, exemplary processes, and so on, which illustrate various exemplary modalities of aspects of the invention. It will be appreciated that the illustrated element limits (for example, boxes, groups of boxes, or other formats) in the Figures represent an example of the limits. Someone of ordinary skill in the art will appreciate that an element can be designed as multiple elements or that multiple elements can be designed as one element. An element shown as an internal component of another element can be implemented as an external component and vice versa. In addition, elements may not be drawn to scale.
    Figure 1 illustrates a continuous digital light processing device (cDLP) for the additive manufacture of an implant.
    Figure 2 illustrates an exemplary graphic representation of wavelength versus magnitude of absorption / emission of light for an initiator, a light source and a dye.
    Figure 3 illustrates an exemplary porous structure support.
    Figure 4 illustrates an exemplary porous structure that includes pores that are oblique.
    Figure 5 illustrates isometric anterior and upper views of an exemplary support.
    Figure 6 illustrates a process for manufacturing a tissue engineering support for implantation in a patient that promotes tissue growth.
    Figure 7 illustrates a process for manufacturing by digital light processing
    4/21 of an implant to be implanted in a patient.
    Detailed Description of the Invention
    Continuous Digital Light Processing
    Figure 1 illustrates a continuous digital light processing device (cDLP) 100 for the additive manufacture of an IMP implant. Device 100 includes a digital micro-mirrored device (DMD) 110. A DMD consists of a matrix of micro-mirrors that controls the intensity of the projected light in each pixel of the layer image, which effectively polymerizes each voxel (volumetric pixel) of each layer. of the IMP implant. The term continuous in continuous digital light processing indicates that all voxels within a layer can be simultaneously projected, as opposed to the successive design (that is, movement of the laser beam) of the voxels that occurs in other additive manufacturing processes, such as like, stereolithography. Additive cDLP manufacturing designs multiple voxels that can add up to a complete implant layer as an image, or voxel mask. This allows the entire layer to be cured simultaneously (ie continuous curing).
    The projector 110 projects the light 120 through a transparent or translucent base plate 130 above which one is a resin 140 that includes a light-curable liquid material. Exposure to light 120 causes resin 140 to cure or polymerize at least partially to form layers of the IMP implant. In the illustrated embodiment, the device 100 additionally includes a construction plate 150 to which the IMP implant is operatively attached. The construction plate 150 operatively attaches to a motor (not shown), the operation of which progressively displaces or raises the construction plate 150 away from the base plate 130 as light 120 successively heals or polymerizes resin 140 to form each layer of the IMP implant. The light 120 further polymerizes or overheats the previously rendered layers to bond or sew the newly polymerized layers to the previous layers.
    In one embodiment, the cDLP 100 device is the Perfactory® UV device produced with envisionTEC (Gladbeck, Germany). In another embodiment, the cDLP 100 device can be a cDLP device in addition to the Perfactory® UV device produced with envisionTEC.
    Accuracy and Resolution
    In one embodiment, each projected voxel mask also uses spatially variable irradiance, which means that each pixel can be assigned a different light intensity value. The benefits of the decade pixel assignment to a different intensity value include the ability to vary cure rates within a layer and which allows for smoothing processes analogous to those found in image processing. In one embodiment, the cDLP 100 device is equipped with an Enhanced Resolution Module (ERM) (not shown) that effectively doubles the resolution within the layer (xy) through a process similar to pixel displacement, a technique that increases the true resolution of devices by moving micro-mirrors in fractions of a pixel in the x and y directions.
    The unique properties of cDLP rendering allow for the enhanced precision defined as the similarity of the resulting implant or support to the format found in the drawing or CAD file. A source of increased precision is found in the plane (x-y) resolution, which is a function of the projector lens magnification and the resolution of the DLP chip. Pixel sizes can be 75 pm or less. ERM, pixel shift, smoothing, or combinations of these can additionally increase the plane resolution by at least a factor of 2.
    The cDLP 100 device additionally provides increased accuracy due to increased inter-plane resolution or (z). The resolution between planes (z) is controlled, among other factors, by the motor (not shown), which moves the construction plate 150 between layers in series. In one embodiment, device 100 has an engine capable of 50 pm increments and as small as 15 pm. The resolution between planes (z) can be further controlled by controlling the light penetration depth 120 to limit the polymerization energy in the resin 140 or previously rendered layers of the IMP implant.
    A model of the Perfactory® UV device has an engine capable of 50 pm increments and a 60 mm lens, which provides a native resolution in the plane (x-y) of 71 pm and 35.5 pm using pixel displacement. In this way, this model of the Perfactory® UV device is capable of continuously polymerizing 35.5 x 35.5 x 50 pm voxels. Another model of the Perfactory® UV device may have a 75 mm lens that can provide a native 42 pm resolution in the plane (x-y) and 21 pm resolution with pixel shift.
    Light Curable Material
    The cDLP process controls the mechanical properties and other properties of the resulting IMP implant, in part, by controlling the molecular weight of the light-curable material. The manipulation of the molecular weight of the material adjusts the strength of the resulting IMP implant, with higher molecular weights that are generally stronger. Thus, for applications where the IMP implant can contain significant mechanical stress, the light-curable material can be chosen, so that the rendered part can properly handle and transmit the mechanical stress.
    In applications such as implants or supports, which are intended for implantation in a patient's body, it is important that the components of the implant or support include the light-curable material, as well as any initiators, dyes, solven6 / 21 tes, and other substances are biocompatible, which means that the implant does not pose a substantial risk of injury or toxicity to living cells, tissues or organs, and does not pose a substantial risk of rejection by the immune system. In some instances, it is possible to use some non-biocompatible components or processes. However, in general, they can be completely removed or become biocompatible before implantation. For example, some non-biocompatible chemicals can be used during the manufacturing process, however, be removed completely before implantation.
    In applications such as tissue engineering structures, resorbability of the support, the ability of the part to decompose in the host body, it is a very important consideration. It is important for tissue regeneration, such as bone, that the support reabsorbed in response to cell maturation and incoming host tissue. Timely resorption of support is important for successful vasculature integration to allow free remodeling and host incorporation of the new tissue. Thus, the reabsorption of predictable support that is important includes predictable rates of loss of material properties, predictable rates of degradation of support (for example, it may be useful to choose polymers that fracture or erode at predictable rates rather than degrade in mass) , and predictable rates of pH change.
    The strength and hardness of the support must be weighed against the resorbability rates of the support. The manipulation of the molecular weight of the material generally adjusts the levels of resorption versus strength of the support with higher molecular weights that result in stronger, but less resorbable supports and lower molecular weights that result in weaker, but more resorbable, supports.
    Low molecular weight polymers are often able to decompose safely and be reabsorbed within the body. In general, resorbable polymers often have low molecular weight compared to polymers used in common automotive, aerospace and industrial applications. Resorbable polymers generally have 2-3 orders of magnitude of lower molecular weight than the polymers used in these applications.
    In addition to being ideally resorbable, the resulting implant can have sufficient green strength to allow post-rendering cleaning of the unpolymerized material from the implant structure that includes its pores. Green strength is defined as the strength of the rendered implant immediately after the cDLP occurs, but before the unpolymerized material is washed, and before any post-curing, such as UV light box exposure or curing based on heat.
    In one embodiment, the cDLP process of the present description uses the resorbable polymer poly (propylene fumarate) or PPF as the light-curable material. PPF incorporates most of the features discussed above for the light curable material
    7/21 which includes low molecular weight, without toxicity and resorbability. In another embodiment, the cDLP process of the present description uses a resorbable light-curable material other than PPF. In yet another embodiment, the cDLP process of the present description uses a light-curable material which, although not resorbable, is biocompatible or bioneutral. In one embodiment, the light-curable liquid material has a molecular weight of approximately 4,000 Daltons or less. In another embodiment, the light-curable or light-curable liquid material has a molecular weight of approximately 1,200 Daltons or less. In yet another embodiment, the light-curable material has a molecular weight in the range of 1,000 Daltons and 20,000 Daltons.
    Viscosity
    Some liquid light curable materials, such as PPF, are highly viscous. In the cDLP, a lost layer can result if insufficient resin 140 is available above base plate 130 or if air bubbles form in this layer due to the excessive viscosity of resin 140 that incorporates the light-curable liquid material. Viscous resins also require a longer pause between layers, as more time is required for the flow within the voids left in the areas where the previous layer was cured.
    The use of a solvent can alleviate these problems by reducing the viscosity of the resin. However, the use of a solvent can affect the rigidity of the implant or support, with higher amounts of solvent that make the implant less rigid. Ideally, the viscosity of the resin can be reduced without sacrificing the rigidity of the implant. In addition, any substance used to reduce the viscosity of the resin may have to have some of the same characteristics described above for the light-curable liquid material including non-toxicity.
    In a embodiment where the light-curable liquid material used in resin 140 is PPF, diethyl fumarate (DEF) is added to resin 140 to reduce the viscosity of the resin. DEF is a precursor of monomers to PPF. This monomer cross-links in the resulting implant or support and once cross-linked presents little or no risk of toxicity. In one embodiment, the ratio between DEF and PPF is 1: 1 by weight. In one embodiment, the ratio between DEF and PPF is 1: 2 by weight. In one embodiment, the ratio between DEF and PPF is 1: 3 by weight. In another modality, the ratio between DEF and PPF is less than 1: 3 by weight. In yet another embodiment, the substance used to reduce the viscosity of the resin is a substance other than DEF. In one embodiment, no substance is added to the resin to reduce the viscosity of the resin.
    Initiator
    The photoinitiators are added to the resin which includes the light-curable liquid material to promote the polymerization reaction. In one embodiment, bis (2,4,68 / 21 trimethylbenzoyl) phenylphosphine (BAPO) trademark Irgacure® 819 (BASF (Ciba Specialty Chemicals)) is used as the initiator. In one embodiment, the percentage by weight of initiator in a resin that includes the light-curable liquid material is in the range of 0.5% and 1.0%. In another embodiment, the percentage by weight of initiator in a resin that includes the light-curable liquid material is in the range of 1.0-2.0%. In another modality, the percentage by weight of initiator in a resin that includes the light-curable liquid material is in the range of 2.0-3.0%. In other embodiments, the percentage by weight of initiator in a resin that includes the light-curable liquid material is lower than 0.5% or higher than 3.0%.
    Dye
    As discussed above, the inter-plane resolution (z) of the cDLP process can be further controlled by controlling the depth of penetration of polymerization light energy into the curable light-curing material or previously cured implant layers. Some level of light penetration into the previously rendered layers may be desired to ensure over-healing or stitching between layers, also known as inter-layer bonding. However, if the light penetrates too deeply, the previously cured layers can overheat resulting in undesired characteristics of the resulting implant or support.
    A property of the chosen dye takes into account its ability to remain suspended in the resin throughout the rendering process. For some dyes, it may be necessary to stop the process and react the resin if the dye settles.
    In one embodiment, a dye is added to the resin that includes the light-curing liquid material to control at least in part the depth of penetration of light from the curing light into the support or implant layers and therefore assist in controlling the bond between -layers. In one embodiment, the dye has some of the same characteristics described above for the light-curable liquid material that does not include toxicity. For example, dyes such as the azo chromium dye that can provide adequate control of the depth of penetration of polymerization light energy into the support or implant layers can be toxic and therefore may not be well suited for implant.
    Since the dye used in a dye initiator package is likely to be incorporated into the support, it may be useful to use dyes that can also positively influence the support surface roughness, act as a bioactive compound, such as an antibiotic or, otherwise, affect the support degradation environment (for example, buffering the pH if it is otherwise too acidic or basic). In one embodiment, a dye used is doxycycline hydrate. In another embodiment, a dye used is amphotericin B.
    9/21
    In one embodiment, titanium dioxide (TiO 2 ) is added to the resin that includes the light-curable liquid material as a dye to control at least in part the depth of penetration of polymerization light energy into the support or implant layers. In another embodiment, a dye other than TiO 2 or a combination of dyes that includes dyes other than TiO 2 are added to the resin that includes the light-curing liquid material to control at least in part the depth of polymerization light energy penetration. in the support or implant layers. In yet another embodiment, no dye is added to the resin that includes the light-curable liquid material.
    Referring again to Figure 1, in one embodiment, the DMD 110 projector projects light 120 upward through the base plate 130 above which is a resin 140 that includes a dye. The dye limits the depth of light penetration 120, thereby improving control of the depth of cure for each individual voxel. The concentration of dye used can be varied to control the depth of light penetration 120. The amount of dye present in resin 140 affects the amount of energy that is imparted to the polymerization reaction.
    The dye limits the depth of polymerization which allows the option to use higher levels of irradiance without losing resolution in the z direction. The current layer can be cured at a high energy level without excessive curing of the previously rendered layers. Using higher levels of light energy in this way can increase the green strength of the implant.
    Dye Initiator Packaging
    Figure 2 illustrates an exemplary graphic representation of the wavelength versus magnitude of light absorption / emission for the initiator, the light source and the dye. The main function of the dye is to block the light. For many dyes, this can be accomplished by absorbing light. For other dyes, this is accomplished by reflecting or scattering light. In this way, the dye will compete with the photon initiator. The area between lines a and b in Figure 2 is the area where the cDLP process has the greatest control over the depth of light penetration and the amount of polymerization energy given to the initiator. The light of a wavelength to the left of line a may not be blocked by the dye. Light of a wavelength to the right of line b may not cause the appropriate polymerization of the resin.
    To further reduce the depth of light penetration, the amount of dye in the resin can be increased. However, it may also be necessary to increase the amount of initiator present as the amount of dye is increased. In this way, the dye and initiator form a dye-initiator package because the amount of one included in the resin may depend on the amount of the other. The graph in Figure
    10/21 is exemplary and other wavelengths of initiator, light source or dye can be used, resulting in a different graph.
    In one embodiment, the concentration of dye in the resin is between 1-5% by weight to reduce the depth of light penetration to approximately 120 pm with layers of 50 pm and 70 pm of over-cure in previously rendered layers. In another embodiment, the concentration of dye in the resin is between 0.01 and 0.2% by weight in the resin. In another embodiment, the concentration of dye in the resin is between 0.2 and 0.5% by weight in the resin. In yet another embodiment, the concentration of dye in the resin is lower than 0.01% or higher than 5% by weight. In one mode, the overheat of previous layers is selected to be in the range of between 10% and 300%.
    Supports
    A support design may include an external shape that fits precisely to a specific patient's defect site. In addition, the design may require complex three-dimensional structures.
    Figure 3 illustrates an exemplary support 300. Support 300 includes pores 310a-c that are orthogonal or at right angles to support 300. The three-dimensional geometry of supports that include internal spaces can be important for loading cells and establishing channels vascular. In one embodiment, a support includes pores or internal channels. In one embodiment, the diameter of pores and channels in the support is between 150 pm and 1 mm. In another modality, the diameter of the pores and channels in the support is between 50 pm and 1.6 mm. In other modalities, the diameter of pores and channels in the support is less than 50 pm or greater than 1.6 mm. The modeling of support pores in these bands may require compensation in CAD to correct, among other factors, post-cure shrinkage of implants or swelling due to moistening caused by the pre-implantation cell culture or by the implantation itself.
    In addition to the supporting design parameters that refer to the pore size, the design may require complex pore structures that facilitate cell loading, growth of new tissue, and intracrescence of host tissue. For example, the design may require that the pores or channels open towards the host tissue at the site of the defect to allow tissue to grow back before total implant degradation. More accurate rendering makes it more likely that complex internal pore structures can be created.
    Figure 4 illustrates an exemplary porous structure support 400. Support 400 includes pores 410a-c that are oblique. Oblique is defined as any direction that is not parallel to the x, y and z directions through which the supports are rendered using the additive manufacturing techniques described above. Oblique construction can be important to ensure that host tissues do not encounter a wall (barrier) in the
    11/21 support, which is more likely when the pore structures are orthogonally constructed than when the pores and / or channels are oriented towards the host tissue. The implant creator may wish to orient the pores and / or channels within a support, so that they open towards the host tissue, thus facilitating the growth of new tissue in the implant and the active incorporation of the implant into the tissues host.
    Additive manufacturing devices with a voxel resolution in the range of 100-1000 pm may be able to produce orthogonally oriented pore structures, however, they may provide insufficient resolution to produce the pores obliquely oriented in these ranges. The resolution of the cDLP device occurs, so that the rendering of structures that have obliquely oriented pores is possible.
    Additionally, in tissue engineering support applications where an initial objective is cell adhesion, the hydrophobic surface of the PPF can be modified through radiofrequency luminescent discharge (RFGD) or by immersing the implant in serum to provide adsorption of proteins. Cell adhesion can also be mediated by other factors incorporated on the surface that mimic the extracellular matrix components. This includes surface roughness, which can include indentations and protuberances that have diameters ranging from 1 nm to 100 pm, as well as material compliance.
    Once adhered, the objective is prone to displace until a cell proliferation and eventually until the maturation as the host tissue integrates. In addition to the effect that the dye has on the surface roughness, other compounds, such as tricalcium phosphate crystals, can be added to the resin in the additive manufacturing device. However, as in the case of the dye, depending on the solubility, the crystal size and the tendency for aggregation, it can be difficult to keep these crystals suspended in the resin at a relatively constant concentration throughout the support rendering process.
    Support design features, such as wall thickness, affect the distribution of macro stress and can be optimized to withstand trauma. In addition, it may be necessary to counterbalance the desired resorption processes with the need for the implant to be loaded during tissue regeneration. The need to locate the tension-containing portions of a support may require consideration of regions without porosity or regions rendered with composite materials, some of which may not degrade.
    Post-Rendering
    The accuracy of the final part may be dependent on the cleaning of the complete post-rendering part. This may be necessary to remove any residual uncured resin that may crosslink after rendering. The choice of washing procedures, in turn, depends on the mechanical integrity of the resin, as cured by the cDLP process or green resistance. The parts that are precisely rendered, however, remain soft can become damaged through improper handling or the use of aggressive solvents. Once cleaned, the resistance of the final part can be improved by post-curing in a UV bath.
    Example 1
    A first modality focused on the calibration of the cDLP additive manufacturing system to produce precisely supports with predictable properties of cell resorption, adhesion and proliferation, host incorporation and tissue regeneration.
    Figure 5 illustrates anterior and upper isometric views, respectively, of an exemplary support 500. The purpose of the calibration study was to calibrate the cDLP system for the additive manufacture of supports with the support plate and column geometry 500. In the modality, the cylindrical test stand was 6.0 mm in diameter and 12.4 mm in length. The diameter of the vertical 510 channels was 800 pm. Plates 520 were 400 pm thick and 800 pm separated from each other. The columns 530 between the plates were 600 µm in diameter. The calibration of the cDLP process consisted of at least six steps.
    The first step in the calibration procedure was to polymerize the single layers of the cDLP resin which includes PPF, DEF, BAPO and the dye. There are at least three variables for study: dye concentration, initiator concentration and irradiance duration. Other factors that can be varied may be the molecular weight of the polymer and the polydispersity, as well as the level of irradiance (that is, the amount and rate at which light is applied). The aim was to have a layer thickness that ensures adequate over-cure between layers, yet to be thin enough to allow for a desired z step size and the generation of precise geometries. The resolution at x, y and z will determine the accuracy of the desired outer and inner pore surface geometry.
    The second step was to ensure that the material properties of the chosen resin configuration provided useful supports. In some cases, the supports will be loaded with cells and / or growth factors and immediately implanted. In other cases, the supports will be precultured (for example, in a bioreactor) before implantation.
    The third step involved the use of the resin to form a purification patch on the base plate in the upper elevator of the cDLP device. For this modality, it was not able to directly cure a debugging application on the construction board. Therefore, the cleaning application was obtained by the over-cure resin on the base plate. The excess cured resin application was then transferred to the building board and cured on this board using a UV bath (Browse ™ 350, 3D Systems) followed by heating with a heat gun. The heat was used to ensure the application center cured in the
    13/21 underlying construction platform as the resin dye content can prevent UV penetration at the application edges. Care has been taken to allow the heated layer and the cooling platform to prevent accelerated curing when the application is reintroduced into the device. This procedure allowed the supports to cure the PPF resin directly, instead of the metal platform itself.
    The fourth step involved transferring the CAD support file to the cDLP device for rendering. The CAD file can contain support structures that span the space between the support and the debugging application. The support structures rise sufficiently above the scrub application to allow the resin to circulate between the scrub application and the support during rendering of the support and to allow washing of the unpolymerized resin that follows this procedure.
    The fifth step involved the rendering of multilayer support, as discussed above.
    The sixth stage involved testing the supports both in vitro and in vivo. In vitro testing includes mechanical testing, biological environments without cells or tissues, and biological environments with cells, growth factors and / or tissues.
    A 1200 Dalton PPF was prepared, synthesized and purified by known procedures. Briefly, DEF (Acros, Pittsburgh, PA) and propylene glycol (Acros) were reacted in a 1: 3 molar ratio with hydroquinone and zinc chloride as a crosslinking inhibitor and catalyst, respectively. This reaction created bis (hydroxy propyl) and ethanol intermediates as a by-product. The intermediate was then transesterified under vacuum to produce poly (propylene fumarate) and propylene glycol as a by-product. PPF was then purified and gel permeation chromatography was used to calculate the average molecular weight (Mn = 1200Da).
    Titanium dioxide TiO 2 R320 (Sachtleben White Plains, NY) which is a 320 nm crystal was used. A 133 pm PPF layer of 4.8% TiO 2 (tested range: 0-4.8%), 2% BAPO (tested range 0.5-2%), 33% DEF (tested range: 33 and 50%), and an irradiance level of 200 mW / dm 2 for 300 seconds (60s and 300s was tested). A lateral spreading (i.e., in x and y) of polymerization beyond the desired layer limits was observed. This area increased more rapidly at higher concentrations of TiO 2 , especially with increased light input at those high dye concentrations. The area of the lateral scattering was not as thick or strongly cured as to the expected exposure area. In order to quantify this phenomenon, an extra step was added to the normal cure test calibration procedure. In addition to measuring the thickness of the cured layer, that is, the z dimension, the xy dimensions were also measured.
    The curing test procedure used a small square test pattern of UV exposure. With each increase in TiO 2 concentration, the length and
    14/21 width of the thin cured square layer were recorded. In addition, the length and width of the total cured area, which includes those areas affected by lateral polymerization, were also measured. With these data, it was possible to calculate the percentage of overheat. The length and width, measurements x and y, were measured for each part, and this process was repeated three times (n = 3) for each concentration of TiO 2 AND BAPO.
    The first attempt produced an incomplete construction and a membrane of polymerized material that formed on the base plate. This was corrected: (1) by regularly filtering the polymerized resin, (2) cleaning the base plate regularly, and (3) monitoring the base plate throughout the 16-hour construction cycle. Cleaning the unpolymerized polymer from the internal pore space of the supports is a simple procedure that uses an ultrasonic alcohol bath. The rendered supports were accurate at 80 qm.
    The polymerization depth (qm) was characterized as a function of titanium dioxide concentration (% by weight) for five different combinations of BAPO concentration (% by weight) and exposure time (s). From these tests, it was determined that a titanium dioxide concentration of 2% by weight with 2% by weight of BAPO and an exposure time of 60s can produce an average polymerization depth equal to 133.3 qm. These configurations, therefore, can be used in the construction of 50-qm layers with 83.3 qm over-cure. An irradiance of 200 mW / dm 2 was used.
    The high refractory index of TiO 2 caused light scattering. Although this dispersion occurs in all directions instead of just in the z direction, the amount of solid layer curing has occurred only in the z direction. There was no intermediate overheat layer in other directions as there were no additional layers on the sides and the layers above the current location did not yet exist. The increase in TiO 2 concentration led to an increased amount of lateral overheat. The test was performed using an irradiance of 200 mW / dm 2 and an exposure time of 300 s. Two levels of BAPO were tested for each concentration of titanium dioxide.
    The cDLP devices used can provide native accuracy of up to 13 qm in z and 71 qm in x and y, and up to 35.5 qm when using smoothing or pixel shift software. This resolution is sufficient to prepare specific implants for the patient. This resolution is high enough that the surface features (eg, surface roughness) can be produced at optimal scales for the cell response.
    Through the use of 1200 Dalton PPF, it became possible to use a cDLP device to produce layers as thin as 60 qm. The resulting highly accurate supports probably allow improvements in the modeling, prediction and eventual design of the specific cell adhesion of the support, proliferation parameters, maturation and reabsorption. The use of dye initiator packaging allows the production of very different resources
    Highly accurate 15/21 with sufficient green resistance to allow aggressive post-rendering removal and handling of unpolymerized resin.
    Example 2
    This modality was implemented in the Perfactory® UV device, which has a 60 mm lens. A relatively small amount of dye was required (for example, 0.01 to 0.2% by weight) of the total resin mass. The dye used in this study is in a higher concentration that is typically used in industrial applications, up to 0.5% of the total polymer mass. It is important that the dye is biocompatible. In this study, a yellow chromium azo dye was used. The amount of primer used in this study was 2% Irgacure® 819 (BASF (Ciba), Florham Park, NJ). The substance used in this study to reduce the viscosity of the resin was diethyl fumarate (DEF), the PPF monomer precursors.
    The projected plate thickness and column diameter (that is, in CAD software) were 0.4 mm and 0.6 mm, respectively. The ten-plate supports generated had an average plate thickness of 0.43 ± 0.02 mm, and an average column thickness of 0.63 ± 0.01 mm. Resource accuracy (ie, low standard deviation) can be just as important as high accuracy. These features measured slightly above their projected dimensions. Although the resources were slightly larger than expected, there is typically a shrinkage effect that is seen in curing photopolymers that results in resources that are smaller than projected. This effect can be resolved in the cDLP system by manipulating the energy distribution for the voxel and the strategy used in exposing a single set of voxel data. When designing part supports, it is essential to use support geometry that can change to prevent anisotropic shrinkage of the support. If the part is firmly attached to the built platform, the base is unable to shrink while the rest of the support shrinks, leading to anisotropy in the amount of deformation. Due to the fact that someone can guarantee the inter-plane dimensions through the physical translation of the construction and overheating platform, only the plane dimensions need to be corrected (that is, scaled to correct the shrinkage).
    Example 3
    For this modality, the Perfactory device used had a 60 mm lens that provides a native resolution in the 71 pm and 35.5 pm plane that uses pixel displacement. The resorption polymer, poly (propylene fumarate) (PPF), was used. A yellow chromium azo dye was added. The initiator used in this modality was Irgacure® 819 (BASF (Ciba), Florham Park, NJ). The substance used to reduce the viscosity of PPF was diethyl fumarate, the precursor to PPF monomers. The energy settings between planes were calibrated to reach a voxel height of 120 pm using
    16/21 an irradiance of 200 mW / dm 2 , and an exposure time of 120-240 s. The support format was composed in a computer-aided design program (CAD) and 6 were produced using an exposure of 120 s. 2 supports were subsequently produced using an exposure of 240 s. 10 measurements of the total diameter of each support were collected using calipers. The desired support diameter was 6mm.
    The supports (n = 6) produced using the 120 s exposure had the following diameters: 5.83 ± 0.03, 5.83 ± 0.03, 5.85 ± 0.04, 5.82 ± 0.02 , 5.83 ± 0.02, and 5.85 ± 0.03 mm. The supports (n = 2) produced using the 240 s exposure had the following diameters: 6.03 ± 0.03 and 6.02 ± 0.02 mm. The 240 s exposure results showed less shrinkage than the 120 s exposure parts.
    Example 4
    A Perfactory UV device was used to produce porous cylindrical PPF supports with a diameter of 6 mm and a length of 1.2 mm (N = 10) or 12.4 mm (N = 8) with a 2 or 4 minute exposure that uses a plate and column geometry. The computer aided design for this support was produced in layers of 50 pm thick with a curing depth of 120 pm to ensure sufficient over-cure (inter-layer bonding). A yellow chromium azo dye, Irgacure® 819 primer (BASF [Ciba], Florham Park, NJ), and diethyl fumarate were added to the primary material, PPF, and used for the production of support. A 500-195-20 Mitutoyo pachymeter (Aurora, IL) was used to measure support resources. The 12.4 mm supports were scanned by microCT. The 1.2 mm supports were represented by image through the scanning electron microscope (SEM).
    The qualitative analysis of micro-CT images showed anisotropic shrinkage, however, predictable. Qualitative analysis of SEM images showed a decrease in layer margins. The 1.2 mm supports had an average observed column diameter (expected 0.4 mm) of 0.43 mm (0.02 standard deviation) and an average observed plate diameter (expected 0.6 mm) of 0, 63 mm (0.01 standard deviation). The 12.4 mm (4 min. Exposure group) had an average diameter (expected of 6 mm) of 6.03 mm (0.03 standard deviation). Accurate over-cure calibration ensures inter-layer bonding and total formation of minor support resources, 400 pm in this study.
    Example 5
    Poly (propylene fumarate) (PPF) with an average molecular weight (Mn) of 1200 Daltons was synthesized using the two-step process described above. DEF was added at a rate of 1g DEF / 2g PPF to reduce the viscosity of the material. The BAPO photoinitiator (BASF (Ciba), Ludwigshafen, Germany) was added in a concentration of 5, 10 or 20 mg / g of combined PPF / DEF resin mass. The titanium dioxide concentrations used during calibration ranged from 0-48 mg TiO 2 / g PPF / DEF. Carbon dioxide
    17/21 rutile titanium with an average particle size of 300nm (Sachtleben, Duisburg, Germany) was used. In combination with the components listed here, a particular order was useful to promote the mixing process and achieve resin homogeneity more quickly. BAPO was first added to DEF, which has a much lower viscosity than PPF, and was mixed until perfectly dissolved. The PPF was then heated to reduce its viscosity before adding the DEF / BAPO mixture. Care has been taken to avoid excessive temperatures (> 70 ° C) that can cause the polymer to crosslink. Once the PPF / DEF / BAPO mixture was prepared, TiO 2 was added in additional steps to allow calibration of the curing parameters as a function of the TO2 concentration.
    The additive manufacturing device based on cDLP used for this study was the Perfactory® Mini Multi Lens (envisionTEC, Ferndale, Ml), which was operated in UV mode. Curing tests were performed to determine the relationship between TO2 concentration and the thickness of the cured layer. To perform each test, a few drops of resin were placed on a glass slide. The Perfactory device was used to cure the resin with a fixed irradiance and time using a square test pattern. An irradiance of 200 mW / dm 2 was used for these tests, and care was taken to calibrate the added thickness of the glass slide. An exposure time of 60 or 300 s was used. After the specified period of time had elapsed, the excess uncured polymer was removed from the slide leaving only the solid square test pattern. A razor blade was used to remove the thin layer of the blade, and digital calipers were used to measure the thickness of the layer. Three copies were made for each unique combination of BAPO and TiO 2 concentrations evaluated.
    Example 6
    The resin was prepared using a 1g DEF / 2g PPF ratio. 20mg BAPO / g resin and 10 mg TiO 2 / g resin were used. Successful construction requires proper adhesion of the cured resin to the building board as the initial layers are cured. Some difficulty was encountered in obtaining adhesion between the PPF resin and the construction platform that uses standard industrial processes, and some intervention was required. A thin base plate was first produced using 50 pm layers, which do not adhere properly to the construction platform, but instead remain attached to the transparent base. The thin plate was carefully removed from the base using a razor blade and placed directly in the center of the construction platform outside the Perfactory device. Care was taken to remove any air trapped between the base plate and the platform. The base plate was then cured for 20 minutes in a UV bath. In addition to the UV exposure, a heat gun was used to finish curing the base plate in order to obtain a strong bond with the construction platform. The supply of a pre-fixed base plate generated from the PPF resin provided the
    18/21 Proper adhesion of desired parts during subsequent construction. Once this step was completed, the test stands were built using an irradiance of 200 mW / dm 2 and an exposure time of 150 s.
    Some post-processing of the test parts was necessary. The test parts were rinsed first with acetone and then with 200-privet ethanol to remove any excess uncured resin from the internal pore spaces. Compressed air was also used to clean the test stands. Once the parts were free of the uncured resin, the construction platform was placed in a UV bath and an additional 2 h of exposure was applied to fully cure the resin and strengthen the parts. The base plate was then separated from the construction platform, and the individual test stands were removed from the base plate. The holders were removed using a razor blade.
    The resin used to produce the total supports was decreased by adding DEF to increase the 1: 1 concentration of PPF / DEF. This was necessary as the resin viscosity increased due to the material's self-curing. The concentrations of BAPO and TiO2 were effectively reduced in this process to 15 mg of BAPO / g of resin and 0.75 mg of TiO2 / g of resin. A pre-fixed base plate was used as described above. The supports were produced using an irradiance of 200 mW / dm 2 and an exposure time of 150 s. After the construction process was completed, the supports were removed from the construction platform and rinsed with 200-proof ethanol. The additional cleaning involved alternating steps of rinsing with ethanol, the use of compressed air, and ultrasonic cleaning in ethanol. The use of acetone was avoided as it was found to damage the test stands. Once the excess resin was removed from the supports, they were placed in a UV bath for 2 h. The holders were removed using a razor blade.
    Bone marrow was obtained from adult human volunteers. Primary cultures of isolated hMSCs have been disseminated. The primary isolates of hMSCs were subcultured at a density of 250,000 per culture flask. The hMSCs were treated with trypsin. The cells were counted and the dense cell infusate was prepared in 32.5 million cells / 2ml for dissemination of supports. Four PPF supports were produced, sterilized with ethylene gas oxide (140 S F), and pre-moistened by immersion in 10% fetal bovine serum for 12 hours. The number of hMSCs loaded on each support was 3.25 million (the optimal cell spread density was based on the estimated cell diameter and the support surface area). 200 pL of hMSC infusate was superimposed on the supports on a multi-well plate (low adhesion plastic) with micropipette. The plate was placed in a vacuum chamber that was quickly pumped downwards in 25 Hg for 1 min. The supports loaded with infusate of
    19/21 high density cells were then incubated for two hours to facilitate cell adhesion.
    At the end of two hours, the wells were filled with culture medium (DMEMLG with 10% fetal bovine serum) to prevent drying. The supports were sequentially collected at four time intervals: 6, 24, 30 and 48 hours. All supports were fixed with 1% glutaraldehyde solution for 30 minutes and then rinsed and stored in phosphate buffered saline (PBS) at 4 degrees centigrade for Scanning Electron Microscopy (SEM).
    The exemplary processes can be better evaluated with reference to the flowcharts of Figures 6 and 7. Although for purposes of simplicity of explanation, the methodologies illustrated are shown and described as a series of blocks, it must be assessed that the methodologies are not limited by order of the blocks, as some blocks can occur in different orders or simultaneously with other blocks from those shown or described. In addition, less than all illustrated blocks may be required to implement an exemplary methodology. In addition, additional or alternative methodologies may employ additional blocks not illustrated. Although Figures 6 and 7 illustrate several actions that occur in series, it should be appreciated that several illustrated actions can occur in a substantially parallel manner. Although numerous processes are described, it must be considered that a greater or lesser number of processes can be employed.
    Figure 6 illustrates a process 600 for manufacturing a tissue engineering support for implantation in a patient and promoting tissue growth. The process 600 includes, in 610, receiving data representing the tissue engineering support in an additive manufacturing device of Digital Light Processing (DLP) that includes a Digital Micro-Mirror Device (DMD). In 620, process 600 also includes activating the DMD to project the light that corresponds to the support layers on a transparent or translucent plate on top of which a construction plate and a biocompatible resin that includes a light-curing liquid material that has it is reabsorbable after polymerization. In 630, process 600 further includes displacing the building plate in selected increments, so that the projected light causes the portions of the resin to polymerize at least partially to substantially resemble the support layers.
    Figure 7 illustrates a process 700 for manufacturing by continuous digital light processing (cDLP) of an implant to be implanted in a patient. Process 700 includes, in 710, providing an additive manufacturing apparatus that includes a Digital Micro-Mirror Device (DMD) and a transparent or translucent plate. In 720, process 700 additionally includes providing a biocompatible resin that includes a liquid material
    20/21 light curable and an initiator. In 730, process 700 further includes depositing a quantity of the resin on top of the transparent or translucent plate. In 740, process 700 further includes triggering the DMD to expose some amount of resin to light to cure the exposed amount of resin to form an implant layer. In an embodiment (not shown), process 700 additionally includes displacing the produced layer of the implant and depositing an additional amount of resin on top of the transparent or translucent plate.
    At 750, process 700 further includes triggering the DMD to expose at least some additional amount of resin to light to cure at least partially the additional exposed amount of resin to form an additional layer of the implant and to at least partially over-cure at least some layer previous to cause at least some inter-layer bonding between the previous layer and the additional layer. In one embodiment, process 700 additionally includes displacing additional layers of the implant before depositing subsequent additional amounts of resin on top of the transparent or translucent plate, where at least one motor in the additive-manufacturing apparatus causes displacement to occur in increments 75 μm or less. In 760, process 700 additionally includes repeating the DMD drive to expose at least some additional amount of resin step 750 numerous times, as needed, to physically produce the implant layer by layer.
    Although the systems, exemplary processes, and so forth, have been illustrated by describing the examples, and although the examples have been described in considerable detail, it is not intended to restrict or in any way limit the scope of the claims attached to such details . It is certainly not possible to describe every conceivable combination of components or methodologies for the purposes of describing the systems, processes, and so on, described in this document. Additional advantages and modifications will be readily apparent to those skilled in the art. Therefore, the invention is not limited to specific details, and to illustrative examples shown or described. Accordingly, this application is intended to cover changes, modifications and variations that are within the scope of the attached claims. In addition, the foregoing description is not intended to limit the scope of the invention. Preferably, the scope of the invention should be determined by the appended claims and their equivalents.
    Insofar as the term includes or includes is used in the detailed description or in the claims, it is intended to be inclusive in a similar way to the term you understand as the term is interpreted when used as a transitory word in a claim. Furthermore, to the extent that the term is either used in the detailed description or in the claims (for example, A or B) it is intended
    21/21 meaning A or B or both. When applicants intend to indicate only A or B, but not both, then the term only A or B, however, not both will be used. Thus, the use of the term or in this document is inclusive, not exclusive. See, Bryan A. Garner, A Dictionary of Modern Cool Usage 624 (2nd. Ed. , 1995).
    1/3
    权利要求:
    Claims (15)
    [1]
    1. Process of manufacturing a tissue engineering support for implantation in a patient and that promotes tissue growth, the process FEATURED for understanding:
    receiving data representing at least tissue engineering support in an additive manufacturing device for digital light processing (DLP) that includes a digital micro-mirror device (DMD);
    activate the DMD to project the light corresponding to the support layers on a transparent or translucent plate above which is provided a construction plate and a biocompatible resin that includes a light-curable liquid material that is resorbable after polymerization; and moving the building plate in selected increments, so that the projected light sequentially causes the portions of the resin to polymerize at least partially to resemble substantially the support layers.
    [2]
    2. Process according to claim 1, CHARACTERIZED by the fact that the displacement of the building plate in selected increments raises the building plate in increments of 50 pm or less.
    [3]
    3. Process according to claim 1, CHARACTERIZED by the fact that the resin includes a dye and an initiator and the ratio between the dye and the initiator is selected to control the penetration of light, so that the overheat of at least one layer previously produced is in at least a range between 10% and 50% and a range between 40% and 100% of the layer thickness.
    [4]
    4. Process for manufacturing by continuous digital light processing (cDLP) of an implant to be implanted in a patient, the CHARACTERIZED process for understanding:
    providing an additive manufacturing apparatus that includes a digital micro-mirror device (DMD) and a transparent or translucent plate;
    providing a resin that includes a light-curable liquid material and an initiator;
    deposit a quantity of the resin above the transparent or translucent plate; triggering the DMD to expose at least some amount of resin to light to cure at least partially the exposed amount of resin to form an implant layer;
    activate the DMD to expose at least some additional resin to light to cure at least partially the additional exposed resin to form an additional layer of the implant and to at least partially over-cure at least some anterior layer to cause at least some bonding between -layer between
    2/3 previous layer and the additional layer; and repeating the DMD to expose at least some additional amount of the resin step a number of times, as needed, to physically produce the implant layer by layer.
    [5]
    5. Process according to claim 1 or 4, CHARACTERIZED by the fact that the polymerization produces the support to include at least one surface that has at least one of:
    indentations and protuberances that have diameters ranging from 1 nm to 100 pm, and pores having openings with diameters in the range of 50 to 1600 pm.
    [6]
    6. Process according to claim 1 or 4, CHARACTERIZED by the fact that the process produces a porous implant that has pores oriented in an oblique orientation.
    [7]
    7. Process according to claim 1 or 4, CHARACTERIZED by the fact that the light-curable liquid material has a molecular weight of at least one of: less than 4,000 Daltons or less than 1,200 Daltons.
    [8]
    8. Process according to claim 1 or 4, CHARACTERIZED by the fact that the resin additionally includes a dye and the ratio between the dye and the initiator in the resin is configured to control the depth of penetration of the light designed to limit the overheat of previous layers.
    [9]
    9. Process according to claim 8, CHARACTERIZED by the fact that the overheat of previous layers is selected to be in the range of between 10% and 300%.
    [10]
    10. Process according to claim 8, CHARACTERIZED by the fact that the dye is titanium dioxide (TiO 2 ) and the initiator is bis (2,4,6-trimethylbenzoyl) phenylphosphine oxide (BAPO).
    [11]
    11. Process according to claim 1 or 4, CHARACTERIZED by the fact that the triggering of the DMD steps projects pixels that are at least 75 pm in size or less.
    [12]
    Process according to claim 4, CHARACTERIZED by additionally comprising:
    displace at least one anterior layer of the implant;
    deposit the additional amount of resin on top of the transparent or translucent plate; and displacing additional layers of the implant before depositing the subsequent additional amounts of resin on top of the transparent or translucent plate, where at least one motor in the additive manufacturing apparatus causes the displacement to occur in increments of 75 pm or less.
    3/3
    [13]
    13. Process for additive manufacturing of a resorbable implant to be implanted in a patient, the process FEATURED for understanding:
    providing a biocompatible resin that includes a light-curable liquid material that is resorbable after polymerization, an initiator, and a dye;
    5 driving an additive manufacturing apparatus to expose a quantity of the biocompatible resin to light to cure at least partially the exposed quantity of resin to form a layer of the resorbable implant;
    activate the additive manufacturing apparatus to expose at least some additional amount of the biocompatible resin to light to cure at least partially the amount
    10 further exposed the biocompatible resin to form an additional layer of the resorbable implant and at least partially over-cure the previously cured layers to cause at least some inter-layer bonding between the previously cured layers and the additional layer; and repeating the activation of the additive manufacturing apparatus to expose at least some additional amount of the biocompatible resin step a number of times as necessary to physically produce the resorbable implant layer by layer, where the ratio between the dye and the initiator is selected to control the depth of light penetration.
    [14]
    14. Process according to claim 13, CHARACTERIZED by the fact that
    20 that the depth of penetration of the light controls at least in part the overheating of the previously cured layers.
    [15]
    15. Implant, CHARACTERIZED by the fact that it is produced by the process defined in any one of claims 1 to 14.
    1/6
    100
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    同族专利:
    公开号 | 公开日
    BR112013003863A2|2016-07-05|
    EP2605805A4|2017-08-16|
    MX366709B|2019-07-22|
    US20150314039A1|2015-11-05|
    EP2605805B1|2019-01-09|
    MX2013002049A|2013-09-26|
    CA2808535A1|2012-02-23|
    US20130304233A1|2013-11-14|
    JP6027533B2|2016-11-16|
    EP3511027A1|2019-07-17|
    JP2013542750A|2013-11-28|
    US9688023B2|2017-06-27|
    KR101879438B1|2018-08-17|
    CN103379924A|2013-10-30|
    US10183477B2|2019-01-22|
    CN103379924B|2015-07-29|
    WO2012024675A9|2013-02-07|
    KR20140036122A|2014-03-25|
    EP2605805A2|2013-06-26|
    CA2808535C|2017-10-03|
    WO2012024675A3|2012-05-31|
    WO2012024675A2|2012-02-23|
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    法律状态:
    2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2018-04-17| B06I| Publication of requirement cancelled [chapter 6.9 patent gazette]|
    2018-04-24| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2018-07-10| B16A| Patent or certificate of addition of invention granted|
    优先权:
    申请号 | 申请日 | 专利标题
    US37535310P| true| 2010-08-20|2010-08-20|
    US61/375,353|2010-08-20|
    US201161491194P| true| 2011-05-29|2011-05-29|
    US61/491,194|2011-05-29|
    PCT/US2011/048620|WO2012024675A2|2010-08-20|2011-08-22|Continuous digital light processing additive manufacturing of implants|
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