US20070009606A1 - Manufacturing process, such as three dimensional printing, including binding of water-soluble material followed by softening and flowing and forming films of organic-solvent-soluble material - Google Patents

Manufacturing process, such as three dimensional printing, including binding of water-soluble material followed by softening and flowing and forming films of organic-solvent-soluble material Download PDF

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US20070009606A1
US20070009606A1 US11127298 US12729805A US2007009606A1 US 20070009606 A1 US20070009606 A1 US 20070009606A1 US 11127298 US11127298 US 11127298 US 12729805 A US12729805 A US 12729805A US 2007009606 A1 US2007009606 A1 US 2007009606A1
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solvent
organic
soluble
soluble material
particles
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Abandoned
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US11127298
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James Serdy
Emanuel Sachs
Thomas West
Sunil Saini
Jie Cai
Andrea Caruso
John Sharobiem
Peter Materna
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Massachusetts Institute of Technology
Theken Spine LLC
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Massachusetts Institute of Technology
Therics LLC
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56Porous materials, e.g. foams or sponges
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    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/28Bones
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    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54Biologically active materials, e.g. therapeutic substances
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00Processes of additive manufacturing
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
    • B33YADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00Materials specially adapted for additive manufacturing
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
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    • A61F2002/30001Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
    • A61F2002/30003Material related properties of the prosthesis or of a coating on the prosthesis
    • A61F2002/3006Properties of materials and coating materials
    • A61F2002/30062(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
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    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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    • A61F2002/30199Three-dimensional shapes
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    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
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    • A61F2002/30225Flat cylinders, i.e. discs
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    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/30767Special external and/or bone-contacting surfaces, e.g. coating for improving bone ingrowth
    • A61F2/30771Special external and/or bone-contacting surfaces, e.g. coating for improving bone ingrowth applied in original prostheses, e.g. holes, grooves
    • A61F2002/30772Apertures or holes, e.g. of circular cross section
    • A61F2002/30784Plurality of holes
    • A61F2002/30785Plurality of holes parallel
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • A61F2/30Joints
    • A61F2/3094Designing or manufacturing processes
    • A61F2002/30985Designing or manufacturing processes using three dimensional printing [3DP]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2210/00Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2210/0004Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
    • AHUMAN NECESSITIES
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    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2230/00Geometry of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2230/0063Three-dimensional shapes
    • A61F2230/0069Three-dimensional shapes cylindrical
    • AHUMAN NECESSITIES
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    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
    • A61F2310/00179Ceramics or ceramic-like structures
    • A61F2310/00293Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, E.G. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2310/00Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
    • A61F2310/00005The prosthesis being constructed from a particular material
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    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412Tissue-regenerating or healing or proliferative agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION, OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS, OR SURGICAL ARTICLES
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432Inhibitors, antagonists
    • A61L2300/434Inhibitors, antagonists of enzymes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B33ADDITIVE MANUFACTURING TECHNOLOGY
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    • B33Y80/00Products made by additive manufacturing
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
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    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/15Sheet, web, or layer weakened to permit separation through thickness
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24273Structurally defined web or sheet [e.g., overall dimension, etc.] including aperture
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/31504Composite [nonstructural laminate]

Abstract

The invention includes biostructures which may be characterized as having substantially all of the organic-solvent-soluble material in the form of a network of irregularly shaped perforated films. The biostructure may further include particles of a substantially-insoluble material, which may be a member of the calcium phosphate family. The biostructure may be osteoconductive. The biostructure may further contain an Active Pharmaceutical Ingredient or other bioactive substance. The API may be a substance which stimulates the production of bone morphogenetic protein, such as Lovastatin or related substances, thereby making the biostructure effectively osteoinductive. One or more of the polymers may have a resorption rate in the human body such as to control the release of the API. Methods of manufacture are also disclosed.

Description

    CROSS-REFERENCE TO RELATED APPLICATION
  • This application claims the benefit of U.S. Provisional patent application No. 60/570,412, filed May 12, 2004, the disclosure of which is herein incorporated by reference in its entirety.
  • BACKGROUND OF THE INVENTION
  • 1. Field of the Invention
  • The invention pertains to the construction of biostructures for implantation into the human body or for growth of tissue.
  • 2. Description of the Related Art
  • Three-dimensional printing (3DP), described in U.S. Pat. No. 5,204,055, has proven to be useful for creating structures for a variety of purposes including medical applications such as bone substitutes and tissue scaffolds.
  • In the three-dimensional printing process, a layer of powder has been deposited such as by roller spreading, and then a binder liquid has been dispensed onto the powder layer by techniques related to ink-jet printing. Powder particles have been joined together by the action of the binder liquid. Subsequent powder layers have been sequentially deposited and drops of binder liquid appropriately dispensed until the desired three-dimensional object has been created. Unbound powder has supported printed regions during the printing of the article and later the unbound powder has been removed to leave a printed article or a preform for further processing.
  • In 3DP, binding of powder particles has been achieved through any one or more of several mechanisms. One mechanism has been that the binder liquid has sometimes dissolved some of the powder. Then, as the solvent in the binder liquid has evaporated, the material from partially or fully dissolved particles has resolidified so as to form a joined or solid mass of that material. Another mechanism has been that the binder liquid has contained a dissolved binding substance which has been left behind when the volatile part of the binder liquid evaporates, and upon evaporation of the volatile constituent of the binder liquid, the dissolved binder substance has solidified around solid particles or has solidified such that it is connected to solid particles, thereby binding the solid particles together. It has also been possible for both of these effects to occur simultaneously. A typical structure resulting from such processes is shown in FIG. 1. The article shown in FIG. 1 was three-dimensionally printed using a binder liquid (chloroform) which was a solvent for some of the powder particles (polymer). The powder bed also contained particles of a leachable porogen. In this conventional structure there is some basic polymeric structure which is in the form of a film of irregular shape probably representing that fraction of polymer which dissolved into chloroform and then resolidified. In addition, there can be seen to be some approximately spherical polymer particles which are attached to the film structure while still at least somewhat retaining the original shape and appearance which they had prior to application of the liquid solvent. These particles probably represent polymeric particles which did not fully dissolve into the chloroform. All of the material shown in FIG. 1 is polymer.
  • Among the materials of interest to be manufactured into articles by 3DP have been polymers. Polymers, especially polymers of medical interest, have generally required the dispensing of organic solvents from printheads during the 3DP process. Organic solvents such as chloroform have been more difficult to dispense from printheads than water or aqueous solutions, because of the combination of low viscosity and low surface tension which is characteristic of many organic solvents.
  • Chloroform in particular, even when it has been successfully dispensed from a printhead, has exhibited further difficulties which relate to how sharp a feature can be created during three-dimensional printing. First of all, chloroform's unusually small surface tension and viscosity have given it an unusually large tendency to spread by capillary action in a powder bed.
  • Additionally, there has been a difficulty associated with the time scale at which chloroform evaporates. In three-dimensional printing using dissolution-resolidification, there is a dissolution time scale during which the dissolution of powder particles into the dispensed binder liquid solvent occurs, as governed by the physical properties of the solvent and the solute. There has also been a resolidification time scale, which is the time scale for evaporation and which is governed by the vapor pressure and other physical properties of the solvent. For chloroform at or near room temperature, the evaporation time scale has been faster than desired, relative to the time for dissolution of particles into chloroform. Accordingly, in order to achieve sufficient dissolution of powder particles into chloroform during the 3DP process, it has been necessary to print chloroform at a relatively high saturation parameter, such as close to or exceeding unity. Such a high saturation parameter has accelerated bleeding (migration) of binder liquid in the powder bed, which in turn has degraded dimensional resolution of printed features and has made it more difficult to remove unbound powder. For example, bleeding has resulted in powder particles being attached to the printed region which are not really desired to be attached to the printed region. Other difficulties associated with the use of chloroform and similar solvents during three dimensional printing have been the aggressive nature of both the liquid and the vapor of such solvents against components of the machine, and the toxicity of chloroform.
  • Another issue in 3DP has been that 3DP has tended to require adjustment of printing parameters to values which are unique to a particular combination of a powder mixture and a binder liquid being used. If there is interest in many powders or solvents/binders and combinations thereof, then significant effort can be required to determine specific printing parameters. Sometimes even a small change in the formulation of the dispensed liquid has required extensive additional experimentation to establish reliable printing.
  • Porous biostructures made of polymer are disclosed in U.S. Pat. No. 6,454,811, and they were made using a powder bed which contained both water-soluble particles and polymeric particles. Those structures were made by dispensing liquid chloroform from a printhead, which resulted in problems of bleeding of dispensed liquid in the powder bed, and so those articles did not have as sharp a dimensional resolution as might be desired. In U.S. Pat. No. 6,454,811, the liquid chloroform was dispensed onto a bed containing particles of poly lactic co-glycolic acid (PLGA) and a leachable water-soluble porogen, and in some instances also containing particles of an insoluble material. In that process of U.S. Pat. No. 6,454,811, the dispensed liquid was an organic solvent (chloroform) and the polymer particles were the particles which were acted upon (dissolved) by the dispensed liquid. The printed articles of U.S. Pat. No. 6,454,811 (after leaching of the porogen) had a high porosity such as 90%, but those articles were basically rigid and could not undergo any significant deformation without breaking, probably due to the inherent material properties of the PLGA, such as its high glass transition temperature.
  • “Fabrication of porous biodegradable polymer scaffolds using a solvent merging /particulate leaching method” by Chun-Jen Liao et al., Journal of Biomedical Materials Research, Volume 59, Issue 4, pp. 676-681 (2001) discloses forming a porous biostructure starting from a powder mixture of polymer particles and salt, causing flow of liquid chloroform through the powder mixture in a mold, and later dissolving out the salt. However, this uses liquid chloroform, and is limited to the types of geometries which can be produced by molding and similar conventional manufacturing, and does not contain Active Pharmaceutical Ingredient and does not contain any member of the calcium phosphate family, which would be useful for bone growth.
  • Outside of three-dimensional printing, in printing systems which involve toner powders, such as electrophotographic, electrographic, or magnetographic imaging systems, it is known to use solvent vapor fixing (or solvating) as a way to permanently fix the toner powders to the paper, as an alternative to the commonly used methods which involve heat. U.S. Pat. No. 5,834,150 discloses using environmentally acceptable halogenated hydrocarbons for this purpose. However, the application in that patent was to create two-dimensional images, not three-dimensional structures. Solvent vapor has been used in other applications such as preparation of dental preforms using the vapor of liquid methyl methacrylate monomer in conjunction with acrylic cements, as described in U.S. Pat. No. 5,336,700. However, this has not extended to three-dimensional printing. U.S. Pat. No. 5,171,834 discloses molding a part and then exposing it to solvent vapors. None of these patents outside the field of 3DP has involved the use of a leachable porogen for the creation and control of pores.
  • Accordingly, it would be desirable to manufacture polymeric articles using three-dimensional printing without actually having to dispense organic solvent. It would be desirable to make polymeric articles by 3DP without having to spend effort adjusting the printing parameters in response to changes of polymer or binder formulation. It would be desirable to achieve the best possible dimensional resolution in complex three-dimensionally printed polymeric parts. It would be desirable to minimize bleeding during 3DP such as by printing at a low saturation parameter. It would be desirable to minimize the handling of chloroform and similar aggressive solvents and the exposure of 3DP machine components to such solvents. It would be desirable to provide control of porosity. It would be desirable to incorporate multiple material compositions in articles made of organic-solvent-soluble materials.
  • It would be desirable for the biostructure to be osteoconductive and ideally also osteoinductive. It would be desirabale for the biostructure to contain Active Pharmaceutical Ingredient and to release the API at a desired rate. It would also be desirable to make a porous article made at least partly of polymer, which may include macroscopic geometric features, which is capable of undergoing significant elastic deformation without breaking. Such squeezability might make surgical installation easier, reduce the need for on-the-spot shaping during surgery, maintain contact against neighboring tissue to promote tissue integration and ingrowth, etc.
  • BRIEF SUMMARY OF THE INVENTION
  • The invention includes biostructures which may be characterized as having substantially all of the organic-solvent-soluble material in the form of a network of irregularly shaped perforated films. The biostructure may further include particles of a substantially-insoluble material, which may be a member of the calcium phosphate family. The biostructure may be osteoconductive. The biostructure may further contain an Active Pharmaceutical Ingredient or other bioactive substance. The API may be a substance which stimulates the production of bone morphogenetic protein, such as Lovastatin or related substances, thereby making the biostructure effectively osteoinductive. One or more of the polymers may have a resorption rate in the human body such as to control the release of the API. A specific macroscopic geometric design of such a biostructure is disclosed. The biostructure can have high porosity and may be able to undergo large deformations without breaking, and can exhibit at least partial springback from such deformation, at least when made of appropriate polymer. The springback may be substantially instantaneous or may be time-dependent.
  • The invention also includes methods of manufacturing such a biostructure starting from a powder mixture which contains both organic-solvent-soluble material and water-soluble material, and optionally also a substantially-insoluble material. A preform corresponding to the eventual biostructure may be manufactured by three-dimensional printing, which may be done by dispensing water or an aqueous binder liquid onto the powder mixture. The resulting preform may contain a structure of water-soluble material, with that water-soluble structure also holding other particles such as particles of organic-solvent-soluble material and (if present) particles of substantially-insoluble material. Then the organic-solvent-soluble material can be caused to soften and flow as a result of exposure to organic solvent vapor, or exposure to heat, or exposure to a substance in a supercritical or near-critical state. In this way, the organic-solvent-soluble material softens and flows and forms films, which closely follow the surface morphology of the water-soluble structure. Upon removal of the condition which causes softening and flowing, a hardened structure of organic-solvent-soluble material may be formed. This structure may retain substantially-insoluble particles which had been partially held by the water-soluble structure and which are also held by the film of organic-solvent-soluble material. This step may further be followed by dissolving out the water-soluble structure.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • The invention is further described in the following Figures:
  • FIG. 1 shows the microstructure of a device printed by a conventional prior art three dimensional printing process. This microstructure shows both films and identifiable particles joined to the films, all of which are made of polymer.
  • FIG. 2 shows the microstructure of a biostructure of the present invention, in which all of the polymer exists in the form of irregularly shaped perforated films, and in which the biostructure is made entirely of polymer.
  • FIG. 3 shows the microstructure of a biostructure of the present invention, in which all of the polymer exists in the form of irregularly shaped perforated films, and which further contains particles of a substantially-insoluble material, which are attached to the polymeric film structure.
  • FIG. 4 a is a CAD solid model of a macroscopic geometric design of the current invention which includes a large number of channels in various orientations. FIG. 4 b shows a biostructure of the present invention used as a spinal cage insert.
  • FIG. 5 shows a sequence of steps in the of manufacturing methods of the present invention.
  • FIG. 6 shows schematics of microstructures during a progression of states which the preform or the eventual biostructure exhibits at various stages of manufacture, for a preform which comprises only organic-solvent-soluble material and water-soluble material. FIG. 6 a shows the preform after initial manufacture of the preform. FIG. 6 b shows the preform after exposure to solvent vapor. FIG. 6 c shows the biostructure after the dissolution and removal of the water-soluble material.
  • FIGS. 7 a, 7 b and 7 c show the same progression of states for a preform and eventual biostructure which additionally include particles of a substantially-insoluble material.
  • FIG. 8 shows a comparison of nominally similar structures, one produced by conventional printing with chloroform binder liquid and the other produced by water printing followed by exposure to solvent vapor.
  • FIG. 9 shows another such comparison.
  • FIG. 10 compares printed articles in which the powder bed contained sucrose. In one case the dispensed binder liquid was pure water while in the other case the dispensed binder liquid was an aqueous solution of sucrose.
  • FIGS. 11 a, 11 b, and 11 c further illustrate various biostructures produced using described printing parameters.
  • FIG. 12 illustrates in a single view both a macrostructural geometry of a grid, and a microstructure, of the present invention.
  • FIG. 13 shows biostructures which were printed and then were exposed to chloroform vapor in the presence of air, illustrating the formation of capillary stress cracks.
  • FIG. 14 illustrates the microstructure of biostructures made of PCL and TCP which were exposed to chloroform vapor.
  • FIG. 15 illustrates the microstructure of such biostructures which were exposed to heat.
  • FIG. 16 illustrates the microstructure of such biostructures which were exposed to supercritical carbon dioxide.
  • DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
  • Article of Manufacture
  • The biostructure of the invention comprises a network or porous structure comprising an organic-solvent-soluble material which may be or include a polymer. At a size scale under approximately 100 micrometers, the biostructure may be characterized by a geometry or morphology, in which substantially all of the organic-solvent-soluble material such as polymer has the form of a film which is irregularly shaped and perforated. In this geometry or morphology, there is substantially no presence of identifiable particles of organic-solvent-soluble material. This is illustrated in FIG. 2. This can be contrasted with the microstructure of conventional structures made by 3DP as previously illustrated in FIG. 1, which included identifiable particles of the same material as: the film. Another possibility, which is not illustrated in FIG. 2, is that a biostructure of the present invention may still have all of its polymer in the form of irregularly shaped perforated films, but may further contain identifiable particles of a substantially-insoluble material which are attached to the irregularly shaped perforated polymeric film. FIG. 3 illustrates a biostructure with such a microstructure.
  • The biostructure of the present invention can be characterized by a high porosity such as greater than 80% in regions which do contain the network (i.e., regions which are not macroscopic open spaces such as macrochannels). Pores may be less than a maximum size such as 1000 micrometers but may have a pore size distribution with a peak in the size range 50 to 100 micrometers, for example. On a larger size scale, the biostructure of the present invention can have macrochannels and other macroscopic internal features with cross-sectional dimensions of approximately 100 micrometers or larger, which do not contain the aforementioned network of organic-solvent-soluble substance. FIG. 4 shows an example of a macroscopic geometric design of a biostructure according to the present invention, illustrating a complex array of macrochannels and other macroscopic geometric features.
  • In terms of materials, the biostructure may comprise a network of organic-solvent-soluble material which comprises one or more organic-solvent-soluble substances. Organic-solvent-soluble may be considered to mean a solubility which is greater than approximately 1 part in 100 by weight at room temperature. This solubility in an organic solvent may be defined with respect to a particular organic solvent which is of interest for a particular substance or application. Also, the organic-solvent-soluble substance may have a low or negligible solubility in water (solubility less than approximately 1 part in 100 by weight at room temperature, or perhaps less than approximately 1 part in 1000), for organic-solvent-soluble substances other than API. Many API are soluble in at least one organic solvent, and some of those API are also somewhat soluble in water. In cases where the API is present in a small concentration (such as less than 10% by weight) relative to the entirety of the organic-solvent-soluble material, it might not be necessary to require any particular range of values for the aqueous solubility of the API.
  • The organic-solvent-soluble material may be or may comprise a polymer(s) or copolymer(s). A copolymer can comprise a variety of monomer units. As used herein, the term polymer can be understood to also include copolymers. Examples of suitable polymers include polycaprolactone (PCL), the PLGA (poly lactic co-glycolic acid) family, polymethylmethacrylate, and comb polymers. Examples of further suitable polymers include polylactones; polyamines; polymers and copolymers of trimethylene carbonate with any other monomer; vinyl polymers; acrylic acid copolymers; polyethylene glycols; polymers of acrylic acid, methacrylic acid or copolymers or derivatives thereof including esters, such as poly(methyl methacrylate); poly(ethylmethacrylate); poly(butylmethacrylate); poly(isobutyl methacrylate); poly(hexylmethacrylate); poly(isodecyl methacrylate); poly(laurylmethacrylate); poly(phenyl methacrylate); poly(methyl acrylate); poly(isopropyl acrylate); poly(isobutyl acrylate); and poly(octadecylacrylate); polyethylenes; Polylactides; Polyglycolides; Epsilon-caprolactone; Polylacatones; Polydioxanones; other Poly(alpha-hydroxy acids); Polyhydroxyalkonates; Polyhydroxybutyrates; Polyhydroxyvalerates; Polycarbonates; Polyacetals; Polyorthoesters; Polyamino acids and their esters; Polyphosphoesters; Polyesteramides; Polyfumerates; Polyanhydrides; Polycyanoacrylates; Poloxamers; Polysaccharides; Polyurethanes; Polyesters; Polyphosphazenes; Polyacetals; Polyalkanoates; Polyurethanes; Poly(lactic acid) (PLA); Poly(L-lactic acid) (PLLA); Poly (DL-lactic acid); Poly-DL-lactide-co-glycolide (PDLGA); Poly(L-lactide-co-glycolide) (PLLGA); Polycaprolactone (PCL); Poly-epsilon-caprolactone; Polycarbonates; Polyglyconates; Polyanhydrides; PLLA-co-GA; PLLA-co-GA 82:18; Poly-DL-lactic acid (PDLLA); PLLA-co-DLLA; PLLA-co-DLLA 50:50; PGA-co-TMC (Maxon B); Polyglycolic acid (PGA); Poly-p-dioxanone (PDS); PDLLA-co-GA; PDLLA-co-GA (85:15); aliphatic polyester elastomeric copolymer; epsilon-caprolactone and glycolide in a mole ratio of from about 35:65 to about 65:35; epsilon-caprolactone and glycolide in a mole ratio of from about 45:55 to about 35:65; epsilon-caprolactone and lactide selected from the group consisting of L-lactide, D-lactide and lactic acid copolymers in a mole ratio of epsilon-caprolactone to lactide of from about 35:65 to about 65:35; Poly(L-lactide and caprolactone in a ratio of about 70:30); poly (DL-lactide and caprolactone in a ratio of about 85:15); poly(DL-lactide and caprolactone and glycolic acid in a ratio of about 80:10:10); poly(DL-lacticde and caprolactone in a ratio of about 75:25); poly(L-lactide and glycolic acid in a ratio of about 85:15); poly(L-lactide and trimethylene carbonate in a ratio of about 70:30); poly(L-lactide and glycolic acid in a ratio of about 75:25); Gelatin; Collagen; Elastin; Alginate; Chitin; Hyaluronic acid; Aliphatic polyesters; Poly(amino acids); Copoly(ether-esters); Polyalkylene oxalates; Polyamides; Poly(iminocarbonates); Polyoxaesters; Polyamidoesters; Polyoxaesters containing amine groups; Poly(anhydrides); and mixtures, copolymers, and terpolymers thereof. The organic-solvent-soluble material in the biostructure can be resorbable if desired. Polycaprolactone and PLGA are resorbable. The organic-solvent-soluble material can be the same everywhere in the biostructure or it can be different at different places in the biostructure. More than one organic-solvent-soluble substance can be blended together in the biostructure, and the composition or existence of a blend can vary from place to place within the biostructure.
  • The organic-solvent-soluble substance may also include a bioactive substance, although it does not have to. The bioactive substance may in general be any Active Pharmaceutical Ingredient or any other useful bioactive substance. Many Active Pharmaceutical Ingredients are soluble in at least one organic solvent. API may be blended together with polymers, and the polymer may have a resorption time in the human body which corresponds to a desired release time of the API. The biostructure can include a blend or co-deposit of various polymers, copolymers and API.
  • A specific category of bioactive substance of interest is substances which stimulate the production of bone morphogenetic proteins. A known category of such substances is HMG-CoA reductase inhibitors, of which a known category of substances is statins. Statins, which were originally developed for the control of cholesterol, have also been found to be useful for stimulating the production of bone morphogenetic proteins. The presence of such substances in an implant would give the implant properties which are essentially the property of osteoinductivity. Possible members of the statin family which could be used in the present invention include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin, and others, and pharmaceutically acceptable salts, esters and lactones thereof. As far as lovastatin, the substance may be either the beta hydroxylic acid form or the lactone form or a combination of both. It is possible that a resorbable polymer which is blended with the API can have a resporption time in the human body which corresponds to a desired release time for the API. The biostructure may comprise more than one polymer blended with each other, or a polymer and an API blended with each other. If more than one polymer is present, one polymer could be a polymer with desired characteristics such as mechanical characteristics, while another polymer could have desired characteristics of resorption suitable for achieving a desired release characteristic of the API.
  • The biostructure can also comprise a substantially-insoluble material (i.e., substantially insoluble in both water and organic solvents), which may be considered to be a solubility of less than approximately 1 part in 100 by weight at room temperature in both water and organic solvents of interest, or perhaps less than approximately 1 part in 1000. The substantially-insoluble material may exist in the biostructure in the form of particles which are at least partly held in place by the polymeric structure. The substantially-insoluble material which is present in the biostructure can be a substance which contributes to osteoconductivity, so as to be useful for bone growth applications. The substantially-insoluble material may be one or more members of the calcium phosphate family. For example, the substantially-insoluble material may be or may contain tricalcium phosphate, which is resorbable in the human body. The tricalcium phosphate may be or may contain a large percentage (50% or 75%) of beta tricalcium phosphate, which is considered to have desirable resorption characteristics in the human body. There can be more than one substantially-insoluble substance in any combination. The particles of substantially-insoluble material may be sized so that they are generally all larger than a limiting size which provokes a macrophage response in the human body. For example, the particles may substantially all be larger than approximately 10 micrometers.
  • The composition of the substantially-insoluble substance(s) also can vary from place to place within the biostructure, as can the presence/absence and amount of the substantially-insoluble material and the size of the particles and the particle size distribution of the substantially-insoluble material. The composition and amount of the organic-solvent-soluble material can vary from place to place within the biostructure. The presence, absence, composition and amount of Active Pharmaceutical Ingredient can similarly vary from place to place within the biostructure. The pore size and pore size distribution of the biostructure can vary from place to place within the biostructure.
  • The biostructure may further contain any additional substance within its pores, or within macrochannels, or in general within any space which is not otherwise occupied. Such substance may be a bioactive substance such as an Active Pharmaceutical Ingredient. This API can be the same as or different from the API which may be blended (co-deposited) in the polymeric network of the biostructure. Such a substance may be contained within the not-otherwise occupied spaces together with a release-controlling substance such as a gel or a degradable polymer.
  • FIG. 4 a shows a particular design of a biostructure with numerous macroscopic geometric features, which can be made according to the methods described herein. In the design as shown in FIG. 4 a, there are five layers stacked in series, although of course the number of layers could vary. Each layer is composed of two sub-layers which are adjacent to each other. One sub-layer is a grid sub-layer, and the other sub-layer is a post sub-layer. For the five overall layers illustrated in FIG. 4 a, the sequence of connection of the sub-layers is: first grid sub-layer; first post sub-layer; second grid sub-layer; second post sub-layer; third grid sub-layer; third post sub-layer; fourth grid sub-layer; fourth post sub-layer; fifth grid sub-layer; fifth post sub-layer. Of course, if alternatively desired, the structure could instead have a grid sub-layer at both extreme ends, or a post sub-layer at both extreme ends.
  • The grid sub-layer comprises a grid which may have an array of holes therethrough, and the holes may be of substantially square or rectangular cross-section. The grid itself may be thought of as containing bars in two mutually perpendicular directions which may be referred to as the x-direction and the y-direction.
  • The post sub-layer comprises an array of posts extending out in a direction (the z-direction) perpendicular to the grid sub-layer. The posts are of rectangular cross-section and are spaced in a spatial pattern having substantially the same unit spacing as the grid of the grid sub-layer, but the post pattern in the post sub-layer can be offset in both the x-direction and the y-direction relative to the grid in the grid sub-layer. In the post sub-layer, the posts further define channels which criss-cross the post-region sub-layer in two mutually perpendicular directions.
  • The biostructure may have an offsetting of any particular grid sub-layer relative to its nearest-neighbor grid sub-layer in either direction. The posts in any post sub-layer have two ends. As illustrated in FIG. 4 a, in a post sub-layer which connects to a grid sub-layer at each end of the posts, one end of each post connects to x-direction bars in one grid sub-layer, and the other end of each post connects to y-direction bars in another grid sub-layer. At each end of the post, the connections to the particular bars may occur at substantially the middle of a bar segment which makes up a side of a square perforation hole in the grid. As a result, the holes through the grid in one grid sub-layer do not align with the holes through the grid in an adjacent grid sub-layer. This makes the paths through the biostructure in the axial direction (z-direction, perpendicular to the plane of the grid sub-layer) somewhat tortuous rather than straight through. This may be advantageous for the ingrowth and retention of tissue in the biostructure. This is also illustrated in FIG. 4 a. It would also be possible to have such offset in some sub-layers while not having such offset in other sub-layers. It would even be possible to have no offset in any sub-layers.
  • All of the structure which is referred to as posts or grid may itself be porous at a size scale smaller than the overall dimensions of the post, or smaller than the overall dimensions of a hole through the grid.
  • As a result of at least some of the described attributes (the irregularly shaped perforated film microstructure, the macrostructure, and the mechanical properties of polymers such as polycaprolactone), the biostructure of the present invention can have mechanical properties such that the biostructure can undergo a large deformation without breaking and can display at least some resilience (springback). For example, a biostructure of the invention, when made from polycaprolactone in the geometry of FIG. 4 a, can be elastically deformed to strains of at least 10% and can then spring at least partway back to its original shape and dimensions. The springback may be substantially instantaneous or may be time-dependent involving a time period of at least several seconds.
  • As an example, such a deformable biostructure may be a spinal cage insert for a spinal cage. The biostructure may be shaped so that its external shape approximately corresponds to the interior shape of the spinal cage. The biostructure may be sized so that at least some of its external dimensions are slightly larger than the corresponding internal dimensions of the spinal cage. A spinal cage typically has some openings or perforations on some of its side or top or bottom surfaces or walls, especially those surfaces which are intended to touch natural bone. The biostructure may be such that it can be compressed to overall dimensions which will fit slidably within the interior of the spinal cage, but when the biostructure is allowed to expand, the biostructure will bulge out into at least some of the openings in the walls, sides, tops or bottoms of the spinal cage. This is shown in FIG. 4 b.
  • The biostructure may be sterile and may be packaged appropriately to maintain its sterility.
  • Method of Manufacturing
  • The invention also includes methods of manufacturing. The manufacturing may start with mixing together powder particles of at least two different materials to form a powder mixture.
  • As a first material, the powder mixture may include particles of water-soluble material. The water-soluble material may comprise one or more water-soluble substance(s). Water-soluble may be considered to mean having a solubility in water of greater than approximately 1 part in 100 by weight at room temperature. The water-soluble substance(s) may have little or no solubility in at least some organic solvents. Little or no solubility is considered to mean a solubility of less than approximately 1 part in 100 by weight at room temperature, or perhaps less than approximately 1 part in 1000. More specifically, the water-soluble material may have a solubility of less than approximately 1 part in 100 by weight at room temperature, or perhaps less than approximately 1 part in 1000, in at least one organic solvent in which the organic-solvent-soluble material (other than possible API) has a solubility of greater than approximately 1 part in 100 by weight at room temperature. Multiple water-soluble materials may be present in the form of discrete particles of individual water-soluble substances, with the discrete particles being mixed together. Of course, it is also possible for more than one water-soluble substance to be present within individual powder particles, although this is perhaps less likely. If there is more than one kind of particle of water-soluble material, such as particles of individual water-soluble substances, those individual particles may have the same or different particle size, particle size distribution, etc.
  • If the water-soluble material includes more than one water-soluble substance, there may be a less-water-soluble substance and a more-water-soluble substance. (Even more than two water-soluble substances could similarly be used, but discussion is presented in terms of two such substances.) The relative solubilities of the two water-soluble substances, and the proportion by mass between the less water-soluble substance and the more-water-soluble substance, may be chosen so as to give desired behavior during the manufacturing process. The particle sizes and particle size distributions of the less-water-soluble substance and the more-water-soluble substance may be the same or different, and may be chosen to provide desired dissolution behavior. In general, dissolution rate increases with increasing solubility in a particular solvent, and increases with decreasing particle size. In order to encourage preferential dissolution in water of one water-soluble substance as compared to another water-soluble substance, the two water-soluble substances can be chosen so as to have sufficiently different solubilities in water. Preferential dissolution can be further enhanced by the use of a particle size for the more-water-soluble substance which is smaller than the particle size for the less-water-soluble substance.
  • Achieving unequal dissolution rates for different water-soluble substances can be useful for at least one particular reason. While a more-highly-water-soluble substance may be significantly involved in the dissolution/resolidification process based on water, the particles of the less-water-soluble material may continue to exist throughout that process in a fairly intact manner. As a result, the water-soluble structure after binding may be approximately described as particles of the less-water-soluble substance joined to each other by necks which are made primarily of the other, more water-soluble substance(s). Therefore it is likely that, upon completion of the manufacturing of the preform, the particles of the less-water-soluble substance may still have a significant presence in approximately the form in which they were originally supplied in the powder mixture. Thus the less-water-soluble particles as originally supplied in the powder may significantly determine the size and size distribution of the pores which eventually exist in the final biostructure. Achieving this situation may be helped if the amount of relatively quickly-dissolving substance, which is intended to become the necks, is somewhat smaller than or approximately equal to the amount of relatively slowly-dissolving substance (because if the particles of the slowly-dissolving substance are to retain a prominent shape when joined to each other by necks, the necks should have smaller total volume than the particles themselves). It is believed that such a use of two different water-soluble substances of different solubilities gives more control over the pore structure of the eventual biostructure than would be available from dissolution/resolidification of a material having a more uniform solubility, such as of a single water-soluble substance in the powder bed.
  • The solubilities all of the water-soluble substances may be such that all of the water-soluble substances can still dissolve in water in a reasonable duration of time, which is pertinent to a later-described manufacturing step (involving removal of all water-soluble material).
  • Among the many water-soluble materials that could be used as a water-soluble substance in the described process are sugars and salts. The family of salts includes sodium chloride as well as many other substances both inorganic and organic. The family of sugars includes sucrose, fructose and lactose, among others. The choice and proportion of the members of the salt and sugar families can be determined by experimenting with various combinations of substances and properties. Various combinations of these materials have been used to form the powder for 3DP experiments such as are described in the Examples herein.
  • It has been found that particles of sodium chloride have an ability to absorb a certain amount of moisture before they actually begin to form necks which would join particles to each other. This moisture-absorption property may be of some help in limiting the spread of aqueous liquid in the powder bed. The rate of dissolution of sodium chloride in water could be described as moderate among various water-soluble substances which could be used.
  • Among sugars, fructose and sucrose exhibit fairly rapid dissolution in water, which can be useful for forming necks joining particles. In comparison to fructose and sucrose, lactose exhibits slower dissolution in water, and can therefore be useful as the more slowly-dissolving water-soluble substance. It is therefore possible to use two different sugars, one for the more-water-soluble substance and the other for the less-water-soluble substance.
  • As a second material, the powder mixture may also include particles of organic-solvent-soluble material. The organic-solvent-soluble material may comprise one organic-solvent-soluble substance, or more than one individual organic-solvent-soluble substance. The organic-solvent-soluble substance(s) may be one or more polymers or copolymers. The organic-solvent-soluble material may also include a bioactive substance such as an Active Pharmaceutical Ingredient. Many Active Pharmaceutical Ingredients are organic-solvent-soluble substances.
  • The organic-solvent-soluble material may be soluble in an organic solvent of interest, which may be considered to be a solubility greater than approximately 1 part in 100 by weight at room temperature. In defining the term organic-solvent-soluble, reference may be made to an organic solvent of interest for a particular substance or application. An organic solvent of particular interest is chloroform (CHCl3), because of the large number of substances which chloroform is capable of dissolving. Other chlorinated hydrocarbons are similarly of interest, as are still other organic solvents. Other organic solvents include methylene chloride, acetone, alcohols (including ethanol and methanol), ethyl acetate and tetrahydrofuran. Also, the organic-solvent-soluble substance may have a low or negligible solubility in water (solubility less than approximately 1 part in 100 by weight at room temperature, or perhaps less than approximately 1 part in 1000), if the organic-solvent-soluble substance is a substance other than API. However, with reference to API and water, it may be that in cases where the API is present in a small concentration relative to the entirety of the organic-solvent-soluble material, it might not be important what is the aqueous solubility of the API.
  • The particles of organic-solvent-soluble material, or at least some of those particles, may comprise a blend of more than one polymer, or may comprise a blend of a polymer and an API. In a blend of a polymer(s) and an API, the polymer, or one of the polymers, may be resorbable and may have a resorption rate in the body environment which is suitable to provide a desired release characteristic of the API. It is also possible that the organic-solvent-soluble material may comprise some particles of a blended composition comprising more than one substance, mixed with other particles of an individual organic-solvent-soluble substance.
  • Organic-solvent-soluble substances of interest include essentially any polymer which may be of interest for biological applications and which is soluble in a suitable organic solvent. Such polymers may be either resorbable or non-resorbable. Specific polymers of interest include polycaprolactone, members of the poly lactic co-glycolic acid (PLGA) family, polymethylmethacrylate, and comb polymers. Polycaprolactone (Sigma-Aldrich, St. Louis, Mo.) may, for example, have a molecular weight of approximately 60,000 to 65,000 Daltons. What is referred to here as an organic-solvent-soluble material could be a mixture of more than one organic-solvent-soluble substances, either existing as discrete different-composition particles mixed among each other within the powder mixture, or existing as substances which are blended with each other within individual particles. Active Pharmaceutical Ingredients may include a substance which is capable of stimulating the production of bone morphogenetic proteins, as discussed elsewhere herein.
  • As a possible third component, the powder mixture can optionally contain particles of a material which is referred to as substantially-insoluble. The substantially-insoluble material may comprise one or more substantially-insoluble substance(s). Substantially insoluble in both water and organic solvents may be considered to mean having a solubility of less than approximately 1 part in 100 by weight at room temperature, or perhaps less than approximately 1 part in 1000 in both water and an organic solvent which is of interest for the process of exposing to solvent vapor. The substantially-insoluble material can be a member of the calcium phosphate family, so as to be useful for bone growth applications. Examples of such substantially-insoluble substances include ceramics such as bioceramics including members of the calcium phosphate family, which are useful for supporting the ingrowth of bone. For example, the substantially-insoluble material may be or may include tricalcium phosphate, which is resorbable. Tricalcium phosphate may be or may contain a large fraction (greater than 50% or greater than 75%) of beta tricalcium phosphate, which is considered to have desirable resorption characteristics. There can be more than one substantially-insoluble substance. The choice of whether to include an insoluble material such as tricalcium phosphate depends on whether that material is desired in the finished product. The particles of substantially-insoluble material could themselves be porous on a size scale smaller than the dimensions of the particles themselves. Such particles could be impregnated with API and, if desired, also polymer, such as a release-controlling polymer. The particles of substantially-insoluble material may be sized so that they are generally all larger than a limiting size which provokes a macrophage response in the human body. For example, the particles may substantially all be larger than approximately 5 micrometers.
  • The proportions of the various materials in the powder mixture may be chosen with a view toward how they will form structures, such as which types of particles (if any) might be held by or within structures formed by another substance. The particle sizes and particle size distributions of the various categories of materials (water-soluble, organic-solvent-soluble, substantially-insoluble) can be substantially the same as each other or they can be different in such a way as will produce a desired feature in the finished product.
  • Next, the powder mixture may be used to form a preform. Forming the preform may occur by binding together particles of the water-soluble material to each other to form a connected mass, thereby also trapping within or attached to the connected mass particles of the organic-solvent-soluble material and (if present) particles of the substantially-insoluble material.
  • One possible way of forming the preform is by molding. Molding can include using a binder substance, which may be a water-soluble binder substance, suitable to attach at least particles of the water-soluble material to each other. Alternatively, it is possible that simply the presence of water or moisture in some form can cause adherence of the water-soluble material within the powder mixture to form the preform. Some manufacturing techniques such as molding may provide some limited ability to vary the composition of the powder from place to place within the preform.
  • In particular, it is possible to manufacture the preform by three-dimensional printing, which provides a very high degree of control of both local geometry and local composition. The biostructure of FIG. 4 a, which contains a considerable degree of geometric complexity, may be manufactured by three-dimensional printing. The manufacturing sequence which includes three-dimensional printing is illustrated in FIG. 5.
  • Three-dimensional printing may include spreading a layer of the described powder mixture. This layer of the powder mixture may be deposited by roller spreading or by other suitable means. It is possible that a single powder mixture may be used to form the entire preform. Alternatively, in the three-dimensional printing process, it is possible to spread different powder mixtures in different layers of the three-dimensional printing process. Even more localized deposition of powder mixtures is also possible, as described for example in U.S. Pat. Nos. 5,934,343, 6,213,168 and 5,336,480.
  • Different powder mixtures which are deposited in different regions of the preform could differ from each other in any of several characteristics. First of all there could be place-to-place variation in the relative proportion of mass among the three categories of material (water-soluble, organic-solvent-soluble, and substantially-insoluble) which make up the powder mixture. Substantially-insoluble material could be present in some places and absent in other places. Within the category of organic-solvent-soluble material, API could be present in some places and absent in other places. In regard to material which is present, within any material category, there could be variation of (in any combination): relative proportion of individual substances within that category; composition, particle size, particle size distribution of any individual water-soluble substance; composition, particle size, particle size distribution of any individual organic-solvent-soluble substance; composition, presence/absence or amount of any bioactive substance such as Active Pharmaceutical Ingredient; use or non-use of blending within particles of organic-solvent-soluble material, and composition of the blend; presence/absence, amount, composition, particle size, particle size distribution of any of any substantially-insoluble substance.
  • After the depositing of a layer of the described powder mixture(s), a next step may be to deposit onto the powder mixture in selected places an aqueous binder liquid suitable to join particles to other particles. As described elsewhere herein, such a binder liquid can bind particles of the water-soluble material to each other either through dissolution/resolidification, or through deposition of binder substance dissolved in the aqueous binder liquid, or through a combination thereof. The aqueous binder liquid can be either pure water or water with a binder substance dissolved in it. If a binder substance(s) is dissolved in the binder liquid, that dissolved binder substance(s) can be the same as one or more of the water-soluble substances present in the powder mixture, or it could be different. The composition and/or amount of the deposited aqueous binder liquid can vary from one place in the biostructure to another place. Although the deposited binder liquid is described here as being water or an aqueous solution, it could more generally be any liquid in which the organic-solvent-soluble material other than API is not very soluble, as discussed elsewhere herein. (Solubility of API in such liquid may be less of a consideration in cases where the concentration of API relative to the entirety of the organic-solvent-soluble material is small anyway.)
  • As is known in the art, there is a substantial base of experience in dispensing or depositing aqueous binder liquids, including both pure water and aqueous solutions. Of particular interest in the practice of the present invention is limiting the spread of the deposited binder liquid in the powder mixture, so as to produce the sharpest possible printed features and the best dimensional resolution. One way to do this is to deposit the aqueous binder liquid using a relatively low value of the saturation parameter.
  • Parameters which influence three-dimensional printing are often summarized as a quantity called the saturation parameter. If printing is performed with discrete drops, each drop is associated with a voxel (unit volume) of powder or powder mixture which may be considered to have the shape of a rectangular prism. The dimensions of the voxel are the drop-to-drop spacing which may be called delta x, the line-to-line spacing which may be called delta y, and the thickness of the powder layer, which may be called delta z. The voxel contains within it a total volume given by (delta x)*(delta y)*(delta z). In a powder or powder mixture, there is an overall geometric space occupied by the bulk powder or powder mixture, and there is a total of the amount of geometric space actually occupied by the solid material making up the various individual powder particles. The ratio of the second of these quantities to the first is the packing fraction, pf. Also within the voxel is a total amount of empty volume representing the space between powder particles, i.e., space not occupied by powder particles, given by (1−pf)*(delta x)*(delta y)* (delta z). The ratio of the dispensed droplet volume to the empty volume in the voxel is the saturation parameter. The drop volume may be represented by Vd. The saturation parameter is then given by Vd/((1−pf)*(delta x)*(delta y)*(delta z)).
  • In the practice of the present invention, the deposition of the aqueous binder liquid can be done at a saturation parameter such as 50%, 40%, 30% or as small as 10% to 20%. This range of saturation parameter is substantially smaller than what is used in most conventional three-dimensional printing. Printing at such a small value of saturation parameter is useful in improving the dimensional resolution of the printed preform and the eventual biostructure.
  • The two steps of powder layer deposition and binder liquid deposition onto the layer of powder or powder mixture can be repeated as many times as needed, with appropriate deposition patterns at each layer, to produce a desired geometry of the manufactured preform or the eventual biostructure. As described elsewhere herein, variation of powder mixture from layer to layer may encompass variation of any characteristic of any component of the powder mixture.
  • Next, the printed powder bed can be allowed to dry as needed and then unbound powder or powder mixture can be removed, resulting in a preform which corresponds to the eventual biostructure. In the preform, at least some of the particles of water-soluble material are joined to each other to form a water-soluble structure. It is possible that water-soluble material may be joined to other water-soluble material through a combination of solidification of whatever binder substance (if any) may have been dissolved in the binder liquid, or through the at least partial dissolution of water-soluble particles in the powder bed followed by resolidification, or both. It is believed, although it is not wished to be restricted to this explanation, that the water-soluble structure holds the organic-solvent-soluble particles in position while those particles are not yet joined to each other. Similarly, it is believed that if any particles of substantially-insoluble material are present, this same structure will hold the particles of substantially-insoluble material in position during this stage of manufacturing.
  • If a manufacturing method other than 3DP is being used (for example, molding), it may also be possible, within the limitations of such other manufacturing method, to place different powder compositions in different places. Formation of the preform could further include processes which involve removal of material (cutting).
  • Following the manufacturing of the preform, a process may be performed which causes at least some of the organic-solvent-soluble material in the preform to soften and flow and coalesce with other organic-solvent-soluble material in the preform to form films. There are at least three possible processes capable of causing such rearrangement of the organic-solvent-soluble material: exposure to vapor of organic solvents; exposure to heat; and exposure to supercritical or near-critical conditions of an appropriate substance.
  • The first of these methods is that the preform can be exposed to vapor of an organic solvent in which at least some of the organic-solvent-soluble material is soluble. The preform can be exposed to a suitable vapor concentration at a suitable temperature for a suitable time and for suitable values of any other relevant parameters, so as to cause at least some joining of organic-solvent-soluble material to other organic-solvent-soluble material. If less than a sufficient amount of liquid solvent is initially provided in the closed container, all of the liquid solvent will evaporate and the partial pressure of the solvent vapor will be less than it could be at that particular temperature. When a sufficient amount of a liquid solvent is initially provided in a closed container which may also contain air, evaporation of the liquid solvent will occur to form solvent vapor, until the partial pressure of the solvent vapor inside the container reaches a saturation partial pressure which is dependent only on temperature. At that point the concentration of the solvent vapor will remain at a steady value and no additional liquid solvent will evaporate. One possibility is that air may be present in the preform at the start of exposure to solvent vapor and may be present in the container in addition to solvent vapor. Another possibility is that air may be evacuated from the preform and from the container, leaving only solvent vapor. A typical procedure for exposing the preform to solvent vapor would involve creating a known solvent vapor concentration inside a container, and the preform would be placed inside the container for a desired duration of time. If the amount of liquid solvent initially provided inside the container was more than the sufficient amount, so that some liquid solvent would remain inside the container as liquid solvent, the biostructure may be supported in such a way that the biostructure does not contact the liquid solvent region and yet is well exposed to solvent vapor. The solvent may be chloroform, which is a solvent for many polymers and other substances of interest. However, chloroform does have toxic properties which likely require it to be very thoroughly removed from biomedical articles. The solvent may be methylene chloride. There are also other organic solvents whose vapor likely has usefulness for organic-solvent-soluble materials but which are less toxic than chloroform. Such solvents include chlorine-free or halogen-free organic solvents such as acetone, ethyl acetate, acetonitrile, and tetrahydrofuran (THF).
  • It is believed, although it is not wished to be restricted to this explanation, that particles of the organic-solvent-soluble material (such as a polymers, API, etc.) absorb the organic solvent even from the vapor state and thereby become dissolved or at least softened. For example, it is believed that polycaprolactone at room temperature can absorb chloroform vapor to an extent of 3% to 5% by weight. In this regard, since many polymers are not crystalline solids anyway, it is helpful to think of those polymers when not exposed to organic solvent vapors as being very highly viscous liquids. With that understanding, it can be further understood that exposure to and absorption of organic solvent vapor by the polymer results in diluting or softening of the polymer to a condition at which the polymer can flow relatively easily over the already-existing structure such as the water-soluble structure. It is believed that the presence of an organic solvent such as chloroform lowers the effective glass transition temperature of the polymer. It is believed that the absorption of organic solvent vapor makes the organic-solvent-soluble material sufficiently soft or liquid so that the organic-solvent-soluble material rearranges itself to the point where the organic-solvent-soluble material has no remaining particles morphology, and the organic-solvent-soluble material has truly all transformed itself into a morphology of thin films.
  • After the exposure of the particles of the organic-solvent-soluble material to solvent vapor, the preform can be removed from the organic solvent vapor and can be exposed for a sufficient time to conditions of little or no concentration of organic solvent vapor, so that a sufficient amount of the organic solvent which was absorbed into the preform can leave the preform. When the organic solvent leaves the preform, the films of polymer or organic-solvent-soluble substance will harden to form a structure of organic-solvent-soluble material.
  • The exact extent to which it is necessary to remove organic solvent from the preform may depend on the toxicity of the organic solvent used, the intended purpose of the biostructure, and other factors. If the organic solvent cannot be sufficiently removed simply by exposure to clean air, it is possible that residual organic solvent could further be removed by an extraction process using carbon dioxide or another substance with similar properties as discussed elsewhere herein. The extraction could be performed at liquid, near-critical or supercritical conditions.
  • As a second method of causing the organic-solvent-soluble material to soften and flow, it is possible to heat the preform to an appropriate temperature for an appropriate time such that the particles of organic-solvent-soluble material simply melt or soften and flow over surfaces of the structure formed by the water-soluble material. (Again, that water-soluble structure may possibly also include substantially-insoluble material.) The temperature used for heat exposure may be selected so as to avoid causing thermal degradation of the polymers and any other substances present in the organic-solvent-soluble material. If the organic-solvent-soluble material further includes bioactive substances such as one or more API, a temperature for heat exposure may be selected so as to avoid thermal damage to those substances as well. A time duration for heat exposure may also be selected suitable to result in a sufficient degree of softening and flowing of the organic-solvent-soluble material. It is believed that at the appropriate temperature, the softened or liquefied organic-solvent-soluble material will soften and flow and coalesce in a manner similar to that which has already been described for exposure to solvent vapor. When the preform is brought back to a lower temperature, the rearranged organic-solvent-soluble material will harden in its new configuration.
  • A third possibility is that the preform can be exposed to a supercritical or near-critical state of a suitable substance. It is known that certain substances in the supercritical or near-critical state acquire remarkable dissolving properties which are quite different from their dissolving properties at more ordinary conditions. It is believed that when the organic-solvent-soluble substance is exposed to an appropriate substance at supercritical or near-critical conditions, the organic-solvent-soluble material will soften or liquefy and coalesce in a manner similar to that which has already been described for exposure to solvent vapor. Upon removal of the supercritical or near-critical fluid, such as by depressurizing, the organic-solvent-soluble material would harden in its new configuration.
  • In particular, carbon dioxide is a substance whose use in the supercritical or near-critical state may be convenient for causing organic-solvent-soluble substance such as polymer to soften and flow. It is known that CO2 in its supercritical or near-critical state has solubility properties similar to the solubility properties of halogenated hydrocarbons and related organic solvents when they are in the form of ordinary liquids. For example, supercritical CO2 is used for the extraction of caffeine from coffee and tea. Above the critical temperature (31° C. for carbon dioxide) and critical pressure (72.8 atm for carbon dioxide), the supercritical fluid substance experiences a significant increase in solvency, and the solvency is strongly dependent on the pressure. For example, PLGA is believed to be soluble in supercritical CO2. Carbon dioxide is a benign substance with respect to the intended use of the present biostructures. For the purposes of the present invention, the use of supercritical CO2 would obviate the need for exposure of the preform or biostructure to cytotoxic materials such as chloroform, and would also obviate the need for exposure to temperature-sensitive substances to undesirably high temperatures. In addition to or instead of operating with carbon dioxide at conditions which are truly supercritical, it is possible to achieve some of the same solvency properties with carbon dioxide at conditions which are not supercritical but are liquid near the critical point, or possibly even with gas near the critical point.
  • In addition to carbon dioxide, there are also other known substances which have their critical temperature within the range that would be reasonable for working with polymers of present interest, and which exhibit similar properties of solvency at supercritical or near-critical conditions. Examples of such other substances include nitrous oxide, sulfur hexafluoride, and certain hydrocarbons. It is believed that at least some of these other candidate supercritical or near-critical substances are also benign substances for medical applications.
  • It is possible that more than one of the above three processes (exposure to solvent vapor, exposure to heat, and exposure to a supercritical or near-critical substance) could be performed, in any combination and in any sequence, suitably so as to cause the desired organic-solvent-soluble material to other organic-solvent-soluble material. For example, exposure to supercritical or near-critical conditions could be performed at a temperature warm enough so that the temperature also contributes to softening. As another example, if solvent vapor is used but the toxicity of the solvent is such as to require a solvent-removal step using a supercritical or near-critical fluid, it is possible that the supercritical or near-critical fluid step intended primarily for extraction purposes could also result in some additional softening and flowing of the organic-solvent-soluble substance. Further, such a process could be performed at warm conditions.
  • It is further believed, although it is not wished to be restricted to this explanation, that when the particles of organic-solvent-soluble material become dissolved, softened or liquefied as a result of any of the disclosed processes, those particles deform, flow or spread so that the dissolved, softened or liquefied organic-solvent-soluble material contacts and at least somewhat merges with other such material, thereby forming a connected structure of the organic-solvent-soluble material in the form of films. This happens to such an extent that the original particles are no longer recognizable as particles, and the water-soluble structure (which may also include particles of substantially-insouble material) provides a surface/structure upon which the organic-solvent-soluble material can spread when it becomes soft so as to help the organic-solvent-soluble material find other organic-solvent-soluble material and coalesce. It is believed that this new structure of organic-solvent-soluble material which is formed will follow in detail the shape of the surface of the water-soluble structure (which may also include particles of substantially-insoluble material) upon which it formed. This results in the organic-solvent-soluble structure generally being in the form of thin films of complicated geometry such as irregularly shaped and perforated. When the cause of the softening and flowing is removed, the films will harden in that morphology.
  • It is further believed, although again it is not wished to be limited to this explanation, that if particles of substantially-insoluble material are present in the preform, being at least partially held in place by the structure of water-soluble material, those same particles of substantially-insoluble material will also be at least partially captured and held by the structure of organic-solvent-soluble material as the organic-solvent-soluble material rearranges itself. For example, particles of the substantially-insoluble material may be held on only some of their surfaces by the water-soluble structure, and they may have other surfaces which are exposed and are easily able to be covered or grasped by the softened or liquefied organic-solvent-soluble material as the organic-solvent-soluble material rearranges itself. When the cause of the softening and flowing is removed, the organic-solvent-soluble material will harden, and the particles of substantially-insoluble material, or at least most of them, will be grasped by the newly-formed structure of the organic-solvent-soluble material, in addition to still being within the grasp of the water-soluble structure which still exists.
  • It is believed, although again it is not wished to be restricted to this explanation, that there is also a possibility that during dissolution/resolidification of the water-soluble material in making the water-soluble structure, there might be some probability that some of the particles of substantially-insoluble material may become totally encased by the water-soluble structure, which would render those particles unavailable to be grasped by the organic-solvent-soluble material as it rearranges during the softening and flowing process. It would similarly be possible for particles of organic-solvent-soluble material to be similarly encased by water-soluble material and unavailable to join with other organic-solvent-soluble material. It is possible that if printing with water or aqueous solution were performed at a relatively large value of saturation parameter such as between 50% and 1, then there might be an increased probability that some particles of substantially-insoluble material or some particles of organic-solvent-soluble material would become totally encased by the water-soluble structure, which is considered undesirable.
  • It is further believed, although it is not wished to be limited by this explanation, that printing at a somewhat low value of the saturation parameter as disclosed herein may be helpful for the purpose of achieving the situation wherein there is a high probability that particles of the substantially-insoluble material which are engaged by the water-soluble structure and retained by that structure upon removal of unbound powder also have sufficiently exposed bare surfaces which are suitable to be later grasped by the organic-solvent-soluble material during the softening and flowing step. Even at a low value of the saturation parameter there may be some probability that some such encasing of such particles may occur, but it is likely that not as many particles would be encased as would be encased at a higher saturation parameter.
  • Finally, after performance of any one or more of the above processes to cause softening and flowing of organic-solvent-soluble material, the preform can be exposed to water under conditions suitable to dissolve out substantially all of the water-soluble structure. It is possible to use stagnant conditions, stirring, agitation, sonication, etc. or any combination thereof. Typically there would not be significant time limits associated with the process of dissolving out the water-soluble structure. In the example situation in which the water-soluble structure is made of a combination of sucrose and lactose, both substances are sufficiently water-soluble that there should be no problem soaking the preform in water for a sufficient time to remove substantially all of the water-soluble material even including the lactose. It is possible that if the API is present in a small concentration relative to the entirety of the organic-solvent-soluble material, even if the API is somewhat water-soluble but is co-deposited with a much larger amount of polymer, the API may be protected from leaching out during the dissolution of the water-soluble structure. This dissolution process leaves the structure of the organic-solvent-soluble material, which may also contain particles of the insoluble substance if such particles were present in the original powder mixture.
  • These various steps are further illustrated schematically in FIG. 6 for a process which uses a powder mixture which contains only water-soluble material and organic-solvent-soluble material. The illustrations in FIG. 6 (and in subsequent FIG. 7) are applicable for illustrating any of the softening and flowing processes which are described herein. FIG. 6 a shows what the preform looks like after printing with the aqueous binder liquid and drying, before the softening and flowing of the organic-solvent-soluble material. At this stage, particles of water-soluble material, which are shown as grey objects, are shown joined together, such as from dissolution in water followed by resolidification, or from solidification of a binder substance initially dissolved in the binder liquid or both. Thus, the water-soluble material forms a water-soluble structure 620. Individual particles of organic-solvent-soluble material 630 are shown somewhat incorporated into the water-soluble structure 620, but are shown as being separate and distinct from each other because at this stage they would not have been exposed to any process which would make them soften or flow or coalesce.
  • FIG. 6 b illustrates the appearance of the preform after the softening and flowing of the organic-solvent-soluble material. It is believed that the formerly individual particles of organic-solvent-soluble material have coalesced and created a sort of film on the surface of the water-soluble structure 620. The morphology of that film (organic-solvent-soluble structure) is believed to closely follow the morphology of the surface of the water-soluble structure. At this point the preform contains both a structure 620 of water-soluble material and a structure 650 of organic-solvent-soluble material. The two structures are closely intertwined with each other.
  • Finally, the preform may be soaked in water suitably to dissolve out the water-soluble structure 620. The structure which remains is the organic-solvent-soluble material which has rearranged itself into the form of films. The structure 650 which remains is illustrated in FIG. 6 c.
  • The illustrations in FIG. 6 were simplified in that they omitted any particles of substantially-insoluble material. However, for some applications the preform may also contain particles of substantially-insoluble material. For more general applicability, FIG. 7 illustrates how the process works if particles of substantially-insoluble material are included in the powder mixture. FIG. 7 a shows what the preform looks like after printing with the aqueous binder liquid and drying, before softening and flowing. At this stage, particles of water-soluble material, which are colored grey, are shown joined together, as was already discussed for FIG. 6 a, forming a structure 720 of water-soluble material. The organic-solvent-soluble particles 730 are shown somewhat incorporated into the water-soluble structure, but are shown as being separate and distinct from each other because at this stage they would not have been exposed to any process which would make them soften or flow or coalesce with each other. It can also be imagined that an occasional organic-solvent-soluble particle might be completely encased by the water-soluble structure, and one such particle 732 is shown.
  • Similarly, substantially-insoluble particles are shown with hatching. It is believed that at least some substantially-insoluble particles can be held in place partly by the newly-formed structure of organic-solvent-soluble substance. Notably, most of the substantially-insoluble particles 740 are shown being grasped by the water-soluble structure 720 over a part of their surface, and being exposed over some remainder of their surface. It can also be imagined that occasionally a substantially-insoluble particle might be completely encased by the water-soluble structure, and one such particle 742 is shown.
  • FIG. 7 b illustrates the appearance of the preform after softening and flowing of the organic-solvent-soluble material. Just as was discussed in connection with FIG. 6 b, it is believed that the formerly individual particles of organic-solvent-soluble material have merged into each other and created a film structure. At this point the preform contains both a structure of water-soluble material and a structure of organic-solvent-soluble material. Particles of substantially-insoluble material 740 are shown as being partly trapped by the water-soluble structure which originally held them, and at the same time partly trapped by the newly-formed structure of the organic-solvent-soluble material. It is possible that an occasional particle, such as substantially-insoluble particle 742 which is completely encased by the water-soluble structure 720, may not be contacted by the newly-formed organic-solvent-soluble structure. Such a particle is likely to be removed from the biostructure during the later dissolution of the water-soluble structure. It is also possible that an occasional particle, such as organic-solvent-soluble particle 732 which is completely encased by the water-soluble structure, may not have had the opportunity to become incorporated into the newly-formed organic-solvent-soluble structure 750. One such particle 732 is shown in FIG. 7 a and is also shown in FIG. 7 b retaining its original shape. Such a particle is also likely to be removed from the biostructure during the later dissolution of the water-soluble structure.
  • Finally, the preform may be soaked in water suitably to dissolve out the structure formed by the water-soluble material. During this dissolution process, it is possible that isolated particles (if they exist) such as isolated particles 732 of organic-solvent-soluble material or isolated particles 742 of substantially-insoluble material, which became completely surrounded by water-soluble structure, may be removed from the preform. The structure which remains is the rearranged organic-solvent-soluble material 750 also contaning anchored particles of substantially-insoluble material 740 (assuming that substantially-insoluble material was present in the powder mixture). The structure which remains is illustrated in FIG. 7 c.
  • Although the process has been described here primarily in connection with performs which have been made by three dimensional printing, it is possible to use the processes described herein in connection with a preform made by any suitable process, as long as the preform contains a water-soluble structure and particles of a material that is suitable to soften and flow.
  • After the completion of the described manufacturing steps, it is possible to add to the biostructure additional substances which may be bioactive or otherwise useful biologically. Such substances can be added into the pores of the biostructure, or into macroscopic empty space of the biostructure such as macrochannels, or in general into any space which is not otherwise occupied. Such API could be in addition to or instead of API which may already have been blended together with the organic-solvent-soluble material making up the porous structure of the biostructure. Such substances placed in the pores, macrochannels etc. can include Active Pharmaceutical Ingredients and release-governing agents for the Active Pharmaceutical Ingredients. Such substances could include, as described elsewhere herein, API which induce the formation of bone such as HMG-CoA reductase inhibitors; antibiotics; angiogenic factors; and others. Such substances could be added in a form which is at least partially liquid through soaking, infusing, etc. The substance(s) may be liquid due to presence of a solvent, or may be liquid due to heating if it is a typical substance which softens or melts upon increase of temperature, or may be liquid due to cooling to an appropriate temperature if it is a reverse phase substance such as triblock copolymers of the Poloxamer (family. Introduction of such substance in liquid form may be followed by solidification or gelation due to evaporation, due to cooling in the case of a typical substance, due to warming up in the case of a reverse-phase substance, due to polymerization, due to cross-linking, or due to any other such process. If such substances are not significantly damaged by the sterilization process, they can be added before the sterilization process; otherwise they can be added after the sterilization process, under appropriate conditions of sterility.
  • Sterilization of the biostructure may be accomplished by any of several means and sequences in relation to the overall manufacturing process. The overall manufacturing process may include terminal sterilization, such as by electron beam irradiation, gamma radiation, ethylene oxide, or other means. The sterilization process may be chosen and sequenced so as to avoid damaging any Active Pharmaceutical Ingredients or bioactive substances which may already be in the biostructure at the time of sterilization.
  • Either before or after a sterilization process, as appropriate, the biostructure may be packaged in packaging suitable to maintain the sterility of the biostructure for a desired duration of time.
  • Method of use, Applications, and Kit
  • The biostructures of the present invention can be used as substitutes for bone for the repair and healing of osseous defects or for the conduction or induction of bone into a desired area. The biostructure contains geometric features (both pores at a microscopic level and channels at a macroscopic level) which help to make the biostructure osteoconductive, and in some embodiments the biostructure contains substantially-insoluble material which helps to make the biostructure osteoconductive, and in some embodiments the biostructure can contain Active Pharmaceutical Ingredients which effectively make the biostructure osteoinductive. In particular, the biostructures can be used as an insert for a spinal cage such as for spinal fusion (arthrodesis). They can also be used as tissue scaffolds for growth of any sort of tissue either inside or outside the body. The springiness of the biostructures of some embodiments of the invention means that the biostructures might be able to be installed into a confined space by squeezing them and allowing them to spring back and fill space. For example, this could provide continuing contact force between the implant and the neighboring bone or other tissue, which would be helpful for promoting guided tissue growth. Also, a compressible scaffold could be folded or rolled or compressed and delivered to a specified site in the compressed state. Once delivered to the site, the confined scaffold could expand or unfold or configure itself to the shape of a tissue void. This would fit in well with minimally invasive surgical techniques, which emphasize minimizing the size of biostructures at the time they are introduced into the surgical site through openings in the skin. For example, a spinal cage insert could be compressed to smaller dimensions before being inserted into the spinal cage, and could expand to fill the spinal cage after it is in place inside the spinal cage.
  • The springiness could promote a good fit to a bone defect site and could limit undesired migration of the biostructure or micromotion between the biostructure and neighboring tissue. For use with a spinal cage which has openings or perforations in its exterior, the elasticity of the biostructure could be beneficial, in that the elasticity would encourage the biostructure to extend into the openings or perforations thereby bringing the biostructure into closer contact with bone on the outside of the spinal cage. This could reduce or eliminate gaps between the spinal cage insert on the interior of the spinal cage and the natural bone on the exterior of the spinal cage. Reducing or eliminating such gaps should help to promote the growth of bone. Flexibility of the scaffold could also be useful for reconstruction of soft tissue such as ligaments or breast tissue or cosmetic applications or heart, bladder, liver, lung, nerve tissue, etc.
  • The biostructure can be provided as part of a kit which further includes surgical instruments and other useful components and articles. For example, the kit could include insertion or installation tools which are specific to the biostructure being provided. The kit could contain a spinal cage and a biostructure which is a spinal cage insert matched to the spinal cage. Such a kit could further contain a tool for compressing the spinal cage insert prior to the spinal cage insert being inserted into the spinal cage during surgery. The tool could even be such as to maintain the spinal cage insert in a compressed state as the spinal cage insert is being inserted into the spinal cage. For example, the tool could have a thin wall which surrounds the compressed spinal cage insert, and the exterior of the thin wall could fit inside the spinal cage, and could be suitable to be withdrawn after the spinal cage insert is inside the spinal cage, leaving the spinal cage insert in place and able to expand.
  • EXAMPLES
  • The invention is further described but is in no way limited by the following non-limiting Examples.
  • Example 1
  • This Example compares polymer structures which were 3D-printed using the water printing followed by exposure to solvent vapor, against polymer structures which were 3D-printed using conventional dispensing of liquid chloroform onto a powder bed operating using the dissolution/resolidification mechanism. Both powder beds contained a water-soluble porogen for later leaching out as an aid to creating porosity in the finished biostructure. Specifically, this Example compares the microstructures of those two types of samples, as already presented in FIG. 1 and FIG. 2.
  • First of all, FIG. 1 illustrates the microstructure of the structure made by conventional 3DP with dispensed liquid chloroform. The powder used in this case was 80:20 NaCl:PCL. The powder mixture did not include any substantially-insoluble material.
  • What can be observed is that there is first of all some basic polymeric structure, which has the form of a film which is irregularly shaped. This basic polymeric structure is believed to come from polymer material which dissolved in the liquid chloroform, and which then resolidified in the form shown upon evaporation of the chloroform. It is believed that the structure of what is seen as the basic polymeric structure probably was determined by shape of the leachable particles which occupied some of the space in the photographed region during the time that dissolution and resolidification were occurring. In addition, in this photograph there can be seen some approximately spherical powder particles which are attached to the films but still retain the general shape of particles. It is believed that during the processes of dissolution, possible liquid migration in the powder bed, and resolidification, such particles became wetted by the chloroform liquid enough to become attached to the basic polymeric structure upon evaporation of the chloroform. However, those particles never became sufficiently wetted to fully dissolve such that they would completely lose their original shape.
  • FIG. 2 illustrates the microstructure of a biostructure of the present invention. The powder used in this case was 80:20 Sucrose:PCL. The powder mixture did not include any substantially-insoluble material. The liquid dispensed during the 3DP process was pure water.
  • What can be observed is that in the microstructure made by the present invention, substantially all of the polymer has the morphology of a of a film which is irregularly shaped and perforated. This basic polymeric structure is believed to come from polymer material which substantially dissolved or softened upon exposure to the chloroform vapor, and which then resolidified in the form shown upon removal of the chloroform. It is believed that the structure of what is seen as the basic polymeric structure closely follows the surface shape of the leachable (water-soluble structure which occupied some of the space in the photograph during the time that softening and flowing of the polymer was occurring.
  • Most significantly, in FIG. 2 there is essentially no presence of polymer in the form of recognizable particles still having the form that they had when the powder was prepared prior to 3D-printing. It is believed that this complete change of morphology away from the shape of individual particles is achieved because the leisurely nature of softening and flowing during exposure to solvent vapor allows substantially all of the polymeric material to absorb enough solvent vapor to become thoroughly softened and spreadable, and then the softened or liquefied polymer has time to spread along the surfaces of the water-soluble structure until it reaches an equilibrium or fully-spread position. In some of the work done here, especially work in which the saturation parameter is small, the water-soluble structure is truly very irregular on a small scale, displaying the outline of some portion of many individual particles of water-soluble material. When the solvent vapor is removed, the softened and spread polymer then hardens in the morphology shown, which is also very irregular.
  • It has been observed for these typical porous samples (dimensions of the order of 1-2 centimeters maximum) that it is sufficient if they are exposed for several minutes to chloroform vapor (saturated partial pressure at room temperature) in order to achieve softening and flowing of the polymer. Longer exposure times (e.g., hours) are not harmful, but a few minutes of exposure is sufficient.
  • Example 2
  • This example also compares polymer structures repeating essentially the same two printing methods and conditions as were presented and compared in Example 1. However, what is presented in this Example is the macrostructure, rather than microstructure. Two comparisons are presented in this Example.
  • FIG. 8 shows a face or top view of two structures. The two articles shown in FIG. 8 are both related to the structure shown in FIG. 4 a, but they are not exactly identical to each other, since they come from different sub-layers of that structure. Nevertheless, the two articles are of a similar nature and in particular the size scales of the geometric features in the two samples are essentially the same, and so there is validity in comparing the fuzziness or sharpness of the two structures. Again, in this case, the powder mixture did not include any substantially-insoluble material. For this comparison, chloroform printing had to be done with masks and water printing was done with programmed deposition of the droplets. The sample on the right illustrates a structure which is sort of a collection of posts, and is printed by conventional dispensing of liquid chloroform. The sample on the left illustrates a sort of a screen structure and is printed by the process of the present invention. It can be seen that the edge definition and sharpness are noticeably better with the water printing solvent vapor exposure method of the present invention than they are with liquid chloroform printing.
  • FIG. 9 is another comparison of printing by the two different methods. For this comparison, chloroform printing had to be done with masks and water printing was done with programmed deposition of the droplets. The powder mixture did not include any substantially-insoluble material. In both of the illustrations of FIG. 9, the pattern printed is a sort of an elongated grid. The illustration on the left is of an article produced by dispensing liquid chloroform. The illustration on the right is of an article produced by water printing solvent vapor exposure. This comparison shows that sharper printing and better removal of unbound powder are achieved using the method of the present invention, as compared to printing with liquid chloroform.
  • Example 3
  • This example compares printing onto the same powder bed composition with a binder liquid which was pure water and printing with a binder liquid which is a solution of sucrose in water. FIG. 10 shows a macroscopic grid pattern made by each of these two methods. In FIG. 10, the illustration on the left shows a structure formed by printing with a sucrose-water solution, and the illustration on the right shows a structure formed by printing with pure water. In each case, the composition of the powder mixture was 80% sucrose, 20% polycaprolactone. The powder mixture did not include any substantially-insoluble material. The saturation parameter used during printing was about 15% (i.e., volume of dispensed liquid compared to empty volume in the voxel). These photographs are of the preform only, prior to any exposure to solvent vapor or dissolution of the water-soluble structure. It appears that the structure resulting from the printing with the sucrose solution is better held together, and the structure printed with pure water is more flaky. It is believed, although it is not wished to be limited to this explanation, that the presence of the sucrose provides binding with less dependence on dissolution taking place during the 3DP process itself, and results in somewhat better filling of spaces between particles and attachment of particles to each other.
  • It is further believed, although it is not wished to be limited to this explanation, that the aqueous sucrose solution binder liquid has somewhat different wetting characteristics from those of plain water binder liquid. It is believed that the sucrose solution causes more powder rearrangement (powder particles pulling closer to each other during the time when they are wet), which means that the primitive features thus formed pull slightly away from the bulk powder, which results in better distinction between wet (printed) and dry (un-printed) regions, and hence less bleeding, and hence crisper and finer feature definition and also better structural characteristics.
  • Example 4
  • Examples 1 through 3 used a powder bed which contained only water-soluble material and organic-solvent-soluble material. This example (Example 4) demonstrates printing with an aqueous binder liquid (pure water) onto a powder bed which comprised not only polymer and water-soluble material, but also tricalcium phosphate. The composition of the powder mixture was 20 wt % PCL (polycaprolactone), 20 wt % TCP, 30 wt % lactose, 30 wt % sucrose. In this Example, as in certain other Examples where the powder mixture contained both sucrose and lactose, the fractions of sucrose and lactose were equal to each other. After three-dimensional printing, the preform was exposed to solvent vapor. After the exposure to solvent vapor, the sugar was leached out with water. Biostructures made in this manner have a squeezability which can readily be felt, and they also contain tricalcium phosphate for encouraging bone ingrowth, and they also contain macrochannels as illustrated in the photographs which are of an appropriate magnification to show macroscopic features. This biostructure is shown in FIG. 3. The large rough-ball-like object in the lower left of FIG. 3 is a TCP particle. The TCP particle was originally manufactured by spray-drying, which accounts for its surface being rough and even for its surface being, on a very small dimensional scale, porous. In the rest of that photograph, the irregular perforated film structure is a film of polymer (PCL). Other views of articles printed with this powder mixture are shown in FIGS. 11 a, 11 b and 11 c.
  • Example 5
  • FIG. 12 illustrates the large-scale features which are the overall grid shape, which is defined by the 3DP process, and small-scale porosity (which are all the smaller features), which are defined largely by the powder and related softening flowing and leaching steps. FIG. 12 would roughly correspond to either of the preforms shown in FIG. 10, after the softening and flowing of the polymeric material and dissolution of the water-soluble structure.
  • Example 6
  • Two types of solvent vapor exposure experiments were conducted, both of which used solvent vapor which was chloroform at a saturated partial pressure at room temperature, i.e., some liquid chloroform was present at the bottom of the container. In some experiments, air was present in the container giving a total pressure in the container of atmospheric pressure. In those experiments, what the performs were exposed to was a mixture of air and chloroform vapor. In a second group of experiments, air had been evacuated from the container, and the pressure in the container was sub-atmospheric, i.e., there was only the partial pressure of chloroform vapor at room temperature. Similarly, in the second group of experiments air was already gone from the internal pores of the preform before there was exposure of the preform to chloroform vapor. In that situation, what the performs were exposed to was only chloroform.
  • It can be understood that in both of these experiments, the partial pressure of the chloroform vapor to which the preform was exposed was the same, and yet it can also be understood that there was a difference because of the presence or absence of air. In the chloroform-only case, the solvent vapor can enter into all of the various pores of the preform easily and very quickly as soon as the preform and the chloroform vapor are introduced to each other. In the case where air is present, when the preform is introduced into the air+chloroform mixture, the pores of the preform are typically occupied by air at that time. For pores at the surface of the preform, that air is immediately replaced by chloroform−air mixture. However, for pores deep inside the preform, it is necessary for a diffusion process to occur before the initial air in the pores is replaced by the air−chloroform mixture. Such a diffusion process requires some amount of time, and this means that the start of softening and flowing occurs later at pores deep inside the preform than it does at the surface of the preform. It is believed that this non-simultaneous start of softening and flowing sets up stresses between already-softened-and-flowed and not-yet-softened-and-flowed local regions. In this situation samples visibly showed capillary stress cracks which are believed to be caused by the non-simultaneous start of softening and flowing. Such capillary stress cracks were absent from samples which were exposed to pure chloroform vapor excluding air. FIG. 13 shows articles which exhibit capillary stress cracks after having been exposed to chloroform vapor with air present in addition to chloroform vapor. Corresponding parts which were exposed to chloroform vapor absent air did not show any such cracks. It is believed that it is generally preferable to use the second situation (solvent vapor only), in which no air is present and exposure to solvent vapor begins almost simultaneously for pores at all locations within the preform.
  • Example 7
  • Samples were made and tested to compare the results of the three different methods of softening and flowing. All of the samples were made using a powder mixture whose composition by weight was: 20% PCL, 20% TCP, 30% Lactose and 30% Sucrose. Samples were made by three-dimensionally printing upon this powder mixture using pure water as a binder liquid. The saturation parameter used during this printing was 0.35 cc of water per cubic cm of overall space in the powder bed. Therefore, with a powder packing fraction of 0.5, the saturation paramter was about 0.7. After drying, the printed pre-forms had unbound powder removed as is usually done. Then, softening and flowing was performed by one of the three methods discussed herein.
  • Biostructures in which the film-forming was due to solvent vapor were exposed to chloroform vapor at saturation partial pressure at room temperature for 15 minutes.
  • Biostructures in which the film-forming was due to heat were held at a temperature of 95° C. for 5 hours.
  • Biostructures in which the film-forming was due to a supercritical fluid were exposed to supercritical carbon dioxide at a pressure of 100 bar (1470 psi) at 30 C for 45 to 60 minutes.
  • After softening and flowing, all samples were soaked in water to remove the water-soluble structure (i.e., the sucrose and lactose).
  • FIG. 14 shows the microstructure of a biostructure exposed to solvent vapor. FIG. 15 shows the microstructure of a biostructure exposed to heat. FIG. 16 shows the microstructure of a biostructure exposed to supercritical carbon dioxide. It is considered that there are no significant differences in the appearance of the microstructures in the three photographs.
  • As an additional means of evaluation, it was desired to determine if almost all of the TCP (substantially-insoluble) powder particles in the printed-upon regions of the preform was successfully held by the polymer structure of the final biostructure. As just explained, the original powder mixture contained equal parts by weight of TCP and polymer. (The original powder mixture also contained the two types of sugar, but by the time of the finished biostructure those substances had been removed by dissolution.) The desirable situation would be that almost all of the particles of the substantially-insoluble material (TCP) which were held by the water-soluble structure at the preform stage should still be included in the finished biostructure. One way that such particles could fail to be included in the finished biostructure would be if such particles were temporarily attached to the polymer structure but broke off during some intermediate stage such as during harvesting and de-dusting of the preform or during dissolution of the water-soluble structure. Another way that such particles could fail to be included in the finished biostructure would be if, at the preform stage, such particles were completely surrounded or encased by water-soluble structure such that those particles were never touched by polymer as it softened and flowed and formed films. Then, with dissolution of the water-soluble structure, such particles would be completely unattached and would wash out. If negligibly few TCP particles are lost to break-off during the dissolution of the water-soluble structure or associated processing steps, and if any encasing of surrounding of particles by water-soluble structure which might occur does not distort the proportions of particles retained in the final biostructure, then the relative weight ratio of TCP and polymer in the final biostructure should still be close to half TCP half polymer, which was the ratio of TCP to polymer in the formulation of the original powder mixture.
  • The actual ratio of TCP to polymer in the finished biostructures (after dissolution of the water-soluble structure) was determined by weighing individual biostructures, followed by burning out all polymer during ThremoGravimetric Analysis, followed by weighing the remaining material, followed by comparing the weight of the remaining TCP to the original weight of the polylner+TCP biostructure. The peak temperature attained during the TGA process was approximately 700 C, which was sufficient to completely decompose and vaporize the polymer, leaving only TCP, whose mass should be unaffected by exposure to temperatures of approximately 700 C.
  • For the biostructures which were exposed to chloroform vapor, the TCP amounted to 44.56% of the biostructure weight. For the biostructures which were exposed to heat, the TCP amounted to 47.24% of the biostructure weight. For the biostructures which were exposed to supercritical CO2, the TCP amounted to 44.39% of the biostructure weight. It is considered that all of these processes for the softening and flowing of the polymer show good retention of TCP particles, i.e., the TCP fraction is close to the ideal 50% by weight. It is also considered that there is no significant difference among the results of the three processes, in terms of the retention of TCP particles.
  • Further Comments and Summary and Advantages
  • The process of the present invention enables the manufacture of porous biostructures whose networks or structures include materials that are only soluble in organic solvents, and those networks or structures can contain a considerable degree of geometric complexity (which is attainable only through three-dimensional printing). Significantly, this process is performed without involving any dispensing of organic solvent from a printhead, which would have been a step fraught with some technical difficulties and, in the case of chloroform, would have required printing at a saturation parameter which is not conducive to achieving fine feature sizes.
  • The process of the present invention also eliminates the need for the entire operating region of the 3DP machine to be exposed to vapors of organic solvents such as chloroform and eliminates the need for the printhead fluid handling system to be designed for handling liquid organic solvents such as chloroform. In the process of the present invention, the printing parameters are determined largely by the properties of the particles of water-soluble material which can be printed upon with water-based binder liquids.
  • Another feature of this invention which can be appreciated is that it decouples the formation of the polymer films from the three-dimensional printing. In tissue engineering research, many polymers are being experimented with for use as scaffolds. In conventional three-dimensional printing, it is known that adjustments and optimizations often have to be made which are unique to specific polymers and solvents and printing conditions. The method of the current invention obviates such adjustments because the dispensed liquid can always be the same well-characterized liquid, typically water.
  • With the use of any of the disclosed process for softening and flowing of polymer, the forming of the polymer into a structure occurs separately from the 3DP process. This means that the 3DP process can be somewhat standardized based largely on the properties and composition of the water-soluble powder components (the sugars and salts) and their binder liquid (which might be as simple as pure water). The 3DP process will not have to be adjusted each time the polymer may be changed, because the polymer is not really an active participant in the 3DP process, i.e., the polymer undergoes no significant physical or chemical change during the actual 3DP process. The undergoing of significant physical change by polymer occurs separately at a later step, and in a setting which is fairly simple. The principal variable influencing the film-forming process is the time duration of exposure to the solvent vapor or heat or supercritical or near-critical conditions. The use of particles of water-soluble material which is later dissolved out helps to create pores of controlled size, and in particular is helpful for creating high porosity. In particular, the use of a mixture of particles of water-soluble substances, some of which are less water-soluble than others, helps to preserve the size of the less-water-soluble particles as templates for the creation of pores. In a more ordinary dissolution/resolidification situation involving only a single water-soluble substance, it would be more difficult to preserve the size and other geometric characteristics of water-soluble particles as templates for the creation of pores.
  • It can be appreciated that the process of the present invention can involve softening or liquefying substantially all of the organic-solvent-soluble substance such as a polymer (except for a likely small number of such particles which might be entirely encased in the water-soluble structure and would therefore be absent from the finished product anyway). When the softening or liquefying occurs, substantially all of the organic-solvent-soluble material can undergo an essentially complete transformation of morphology. What started out as discrete particles of organic-solvent-soluble material can end up entirely in the morphology of films of organic-solvent-soluble material which are irregularly shaped and perforated. In contrast, conventional printing with an organic solvent binder liquid onto a bed of polymer particles involves dissolution of some (not all) of the polymer into the binder liquid, followed by resolidification of whatever was dissolved, and there is typically some degree of retention of some of the shape of the original polymer particles. The use of vapor of organic solvent accomplishes this softening of the organic-solvent-soluble substance without disrupting the overall placement of the organic-solvent-soluble material to the extent that would likely occur if the preform were to be immersed in or exposed to liquid organic solvent.
  • It is known that there are many polymeric substances, in addition to being substantially insoluble in water, are substantially insoluble in certain other solvents, such as ethanol and other alcohols. It is also known that some substances contemplated for the water-soluble particles, such as members of the sugar family, are soluble in certain other solvents, again, such as ethanol or other alcohols. The general intent as explained herein is that the binder liquid should be a solvent for the water-soluble material but should not dissolve the particles of polymer which are included in the powder mixture. Therefore, it could be contemplated that the binder liquid dispensed during 3DP, which has been described as water or an aqueous solution, could similarly be some liquid other than water which is a solvent for the water-soluble material but still does not dissolve the particles of polymer or similar material which have been referred to herein as organic-solvent-soluble. Such a binder liquid could further contain dissolved substances such as sugars. Such a binder liquid might not be as easy to dispense as water, but still could be used in accordance with the present invention.
  • Similarly, the solvent which is used to dissolve out the water-soluble material near the end of manufacturing, has been described herein as being water; however that solvent could potentially be a liquid other than water if such liquid dissolved the water-soluble structure and did not substantially remove or damage any substance which is desired to remain in the biostructure. With the desired final materials remaining in the biostructure typically being primarily polymers, and possibly polymers which are alcohol-insoluble, and with candidate water-soluble-substances being sugars which have at least some solubility in alcohols, it would be possible to dissolve out the water-soluble substance(s) using a non-aqueous solvent such as an alcohol which leaves the desired biostructure substantially unaffected. Such dissolution might take a longer time than dissolution using water, but it could be done in accordance with the present invention. For example, sucrose, which is quite soluble in water, is also slightly soluble in ethanol. Fructose, which is quite soluble in water, is more soluble in ethanol than is sucrose. Lactose, which is less soluble in water than are sucrose and fructose, is described in the literature as sparingly soluble or very slightly soluble in ethanol.
  • It can be appreciated that the process of causing the organic-solvent-soluble material to soften and flow can be performed, as described in Example 7, until no more rearrangement of organic-solvent-soluble material takes place, and what was originally particles of organic-solvent-soluble material has completely become films. However, it can also be appreciated that, if desired, this process could be carried out only to some intermediate stage in which some melting and flowing has occurred, but the process has not gone entirely to completion. This can be controlled by the time duration of exposure to the softening condition, together with the details of exposure to the softening condition (such as composition and concentration of solvent vapor in the case of exposure to solvent vapor, temperature in the case of exposure to heat, and pressure or temperature in the case of exposure to supercritical or near-critical fluid). For example, it is possible that an Active Pharmaceutical Ingredient of interest, whose time-release may be desirably controlled by the degradation of the organic-solvent-soluble material such as polymer, may be water-soluble to an extent such that it is somewhat removed during the dissolution of the water-soluble structure. In such situation, it may be desirable to include in the powder mixture microbeads which have been made so as to contain central regions of the API surrounded by polymer. Then, the softening and flowing process could be carried out to an extent which results in softening and flowing but not totally exposing the API. In fact, it would be possible to include in the powder mixture particles of a somewhat more-readily flowable organic-solvent-soluble material, together with microbeads as described whose polymer is somewhat less readily flowable. Then, during the softening and flowing step, the more-readily-flowable organic-solvent-soluble material could soften and flow, while the microbeads would survive somewhat intact, in somewhat the same way as the particles of substantially-insoluble material survive intact and are incorporated into the final biostructure. Even more generally, it is possible that some individual particles (or microbeads) in the powder mixture could contain more than one of the following three categories of substances, all within the same powder particle: organic-solvent-soluble substance, water-soluble substance, and substantially-insoluble substance. It is possible for the powder mixture to contain particles of organic-solvent-soluble material of different compositions having unequal tendencies to soften and flow.
  • It can also be appreciated that, in addition to simply exhibiting a large fraction of open space, the resulting biostructure also exhibits a high degree of connectivity (a lot of perforations in the film). It is believed that this feature also is helpful for promoting biological activity and ingrowth of tissue.
  • Any technique described for any individual stage of the processing could be used with any other technique for any other stage, in any combination.
  • The invention may be practiced in ways other than those particularly described in the foregoing description and examples. Numerous modifications and variations of the invention are possible in light of the above teachings and, therefore, are within the scope of the appended claims.
  • The entire disclosure of each document cited (including patents, patent applications, journal articles, abstracts, manuals, books, or other disclosures) in the Background of the Invention, Detailed Description, and Examples is herein incorporated by reference in their entireties.
  • While the invention has been described with reference to particularly preferred examples and embodiments, those skilled in the art will appreciate that various modifications may be made to the invention without departing from the spirit and scope thereof.

Claims (37)

  1. 1. A biostructure which comprises an organic-solvent-soluble network comprising organic-solvent-soluble material at least some of which is in the form of irregularly shaped perforated films, and wherein the organic-solvent-soluble material comprises an Active Pharmaceutical Ingredient and an organic-solvent-soluble material which is not an Active Pharmaceutical Ingredient.
  2. 2. The biostructure of claim 1, wherein the organic-solvent-soluble network defines pores which have a size scale less than approximately 1000 micrometers.
  3. 3. The biostructure of claim 1, wherein the organic-solvent-soluble network further defines macroscopic internal features which are free of the organic-solvent-soluble material, the macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.
  4. 4. The biostructure of claim 1, wherein all of the organic-solvent-soluble material is in the form of irregularly shaped perforated films.
  5. 5. The biostructure of claim 1, wherein the organic-solvent-soluble material which is not an Active Pharmaceutical Ingredient comprises a polymer or copolymer or terpolymer, and wherein the Active Pharmaceutical Ingredient is co-located with the polymer or copolymer or terpolymer, and wherein the polymer or copolymer or terpolymer has a resorption time in the bodily environment which provides a desired release characteristic for the Active Pharmaceutical Ingredient.
  6. 6. The biostructure of claim 1, wherein the organic-solvent-soluble material comprises a copolymer or terpolymer comprising caprolactone and an appropriate number of additional monomers.
  7. 7. The biostructure of claim 6, wherein the additional monomer(s) are selected from the group consisting of glycolide, L-lactide, D-L-lactide, trimethylene carbonate and ethylene glycol.
  8. 8. The biostructure of claim 1, wherein the organic-solvent-soluble material comprises at least one substance selected from the group consisting of polylactones; polyamines; polymers and copolymers of trimethylene carbonate with any other monomer; vinyl polymers; acrylic acid copolymers; polyethylene glycols; polyethylenes; Polylactides; Polyglycolides; Epsilon-caprolactone; Polylacatones; Polydioxanones; other Poly(alpha-hydroxy acids); Polyhydroxyalkonates; Polyhydroxybutyrates; Polyhydroxyvalerates; Polycarbonates; Polyacetals; Polyorthoesters; Polyamino acids and their esters; Polyphosphoesters; Polyesteramides; Polyfumerates; Polyanhydrides; Polycyanoacrylates; Poloxamers; Polysaccharides; Polyurethanes; Polyesters; Polyphosphazenes; Polyacetals; Polyalkanoates; Polyurethanes; Poly(lactic acid) (PLA); Poly(L-lactic acid) (PLLA); Poly (DL-lactic acid); Poly-DL-lactide-co-glycolide (PDLGA); Poly(L-lactide-co-glycolide) (PLLGA); Polycaprolactone (PCL); Poly-epsilon-caprolactone; Polycarbonates; Polyglyconates; Polyanhydrides; PLLA-co-GA; PLLA-co-GA 82:18; Poly-DL-lactic acid (PDLLA); PLLA-co-DLLA; PLLA-co-DLLA 50:50; PGA-co-TMC (Maxon B); Polyglycolic acid (PGA); Poly-p-dioxanone (PDS); PDLLA-co-GA; PDLLA-co-GA (85:15); aliphatic polyester elastomeric copolymer; epsilon-caprolactone and glycolide in a mole ratio of from about 35:65 to about 65:35; epsilon-caprolactone and glycolide in a mole ratio of from about 45:55 to about 35:65; epsilon-caprolactone and lactide selected from the group consisting of L-lactide, D-lactide and lactic acid copolymers in a mole ratio of epsilon-caprolactone to lactide of from about 35:65 to about 65:35; Poly(L-lactide and caprolactone in a ratio of about 70:30); poly (DL-lactide and caprolactone in a ratio of about 85:15); poly(DL-lactide and caprolactone and glycolic acid in a ratio of about 80:10:10); poly(DL-lacticde and caprolactone in a ratio of about 75:25); poly(L-lactide and glycolic acid in a ratio of about 85:15); poly(L-lactide and trimethylene carbonate in a ratio of about 70:30); poly(L-lactide and glycolic acid in a ratio of about 75:25); Gelatin; Collagen; Elastin; Alginate; Chitin; Hyaluronic acid; Aliphatic polyesters; Poly(amino acids); Copoly(ether-esters); Polyalkylene oxalates; Polyamides; Poly(iminocarbonates); Polyoxaesters; Polyamidoesters; Polyoxaesters containing amine groups; Poly(anhydrides); and mixtures, copolymers, and terpolymers thereof.
  9. 9. The biostructure of claim 1, wherein the not-Active-Pharmaceutical-Ingredient has a solubility in at least one organic solvent of at least approximately one part in 100 by weight at room temperature.
  10. 10. The biostructure of claim 1, wherein the not-Active-Pharmaceutical-Ingredient has an aqueous solubility of less than approximately 1 part in 100 by weight at room temperature.
  11. 11. The biostructure of claim 1, wherein the Active Pharmaceutical Ingredient is capable of stimulating bone repair.
  12. 12. The biostructure of claim 1, wherein the Active Pharmaceutical Ingredient is capable of stimulating the production of bone morphogenetic proteins.
  13. 13. The biostructure of claim 1, wherein the Active Pharmaceutical Ingredient is an HMG-CoA reductase inhibitor.
  14. 14. The biostructure of claim 1, wherein the Active: Pharmaceutical Ingredient is a member of the statin family.
  15. 15. The biostructure of claim 1, further comprising particles of tricalcium phosphate or another substantially-insoluble substance.
  16. 16. The biostructure of claim 1, wherein the biostructure further comprises, in at least some space not occupied by any other materials, a biologically useful material.
  17. 17. A preform which comprises a water-soluble structure forming a network, and, partially attached to the water-soluble structure, particles of an organic-solvent-soluble material, the preform having macroscopic channels therethrough, wherein the organic-solvent-soluble material comprises an Active Pharmaceutical Ingredient.
  18. 18. The preform of claim 17, wherein the preform further defines macroscopic internal features which are free of any material, the macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.
  19. 19. A preform which comprises a water-soluble structure forming a network, and an irregularly-shaped perforated film of organic-solvent-soluble material conforming to surfaces of the water-soluble structure, wherein the organic-solvent-soluble material comprises an Active Pharmaceutical Ingredient.
  20. 20. The preform of claim 19, wherein the preform further defines macroscopic internal features which are free of any material, the macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.
  21. 21. A method of manufacturing a biostructure, the method comprising:
    forming at least one powder mixture by mixing particles of an organic-solvent-soluble material and particles of a water-soluble material;
    manufacturing a preform by causing particles of the water-soluble material in the powder mixture to join or adhere to other particles of the water-soluble material to form a water-soluble structure which also contains or holds particles of the organic-solvent-soluble material;
    forming a film of the organic-solvent-soluble material by causing particles of the organic-solvent-soluble material to soften and at least partially flow to conform to surfaces of the water-soluble structure; and
    causing or allowing the organic-solvent-soluble material to harden, wherein forming the film of the organic-solvent-soluble material comprises exposing the preform to a fluid in a supercritical or critical state or at a pressure greater than half the critical pressure of the fluid, under suitable conditions and for a suitable time duration to cause organic-solvent-soluble material in the preform to soften and at least partially flow.
  22. 22. The method of claim 21, wherein the fluid comprises a substance selected from the group consisting of: carbon dioxide; nitrous oxide; sulfur hexafluoride; alkanes; hydrofluoroalkanes; and a mixture of carbon dioxide and an alcohol.
  23. 23. (canceled)
  24. 24. A method of manufacturing a biostructure, the method comprising:
    forming at least one powder mixture by mixing particles of an organic-solvent-soluble material and particles of a water-soluble material;
    manufacturing a preform by causing particles of the water-soluble material in the powder mixture to join or adhere to other particles of the water-soluble material to form a water-soluble structure which also contains or holds particles of the organic-solvent-soluble material;
    forming a film of the organic-solvent-soluble material by exposing the preform to a vapor of an organic solvent in which the organic-solvent-soluble material is soluble, under suitable conditions and for a suitable time duration to cause organic-solvent-soluble material in the preform to soften and at least partially flow to conform to surfaces of the water-soluble structure;
    causing or allowing enough of the organic solvent to escape from the preform so that the organic-solvent-soluble material hardens; and
    exposing the preform to a clean-up solvent suitable to remove residual organic solvent,
    wherein the clean-up solvent comprises carbon dioxide in a pressurized liquid, pressurized gas, critical or supercritical state.
  25. 25. A method of manufacturing a biostructure, the method comprising:
    forming at least one powder mixture by mixing particles of an organic-solvent-soluble material and particles of a water-soluble material;
    manufacturing a preform by causing particles of the water-soluble material in the powder mixture to join or adhere to other particles of the water-soluble material to form a water-soluble structure which also contains or holds particles of the organic-solvent-soluble material;
    forming a film of the organic-solvent-soluble material by causing particles of the organic-solvent-soluble material to soften and at least partially flow to conform to surfaces of the water-soluble structure; and
    causing or allowing the organic-solvent-soluble material to harden, wherein the organic-solvent-soluble material comprises an Active Pharamaceutical Ingredient.
  26. 26. The method of claim 25, wherein the particles of the organic-solvent-soluble material comprise discrete particles of Active Pharmaceutical Ingredient.
  27. 27. The method of claim 25, wherein the particles of the organic-solvent-soluble material comprise particles which contain, co-located with each other, both Active Pharmaceutical Ingredient and a polymer or copolymer or terpolymer.
  28. 28. The method of claim 25, wherein the particles of the organic-solvent-soluble material comprise particles which contain, located in identifiable places within particles, Active Pharmaceutical Ingredient and a polymer or copolymer or terpolymer.
  29. 29. The method of claim 25, further comprising, after all of the above steps, infiltrating a biologically useful substance into the biostructure.
  30. 30. The method of claim 25, wherein the powder mixture further comprises particles of tricalcium phosphate or another substantially-insoluble substance.
  31. 31. The method of claim 25, wherein the particles of organic-solvent-soluble material contain an Active Pharmaceutical Ingredient which is not soluble in an organic solvent.
  32. 32. The method of claim 25, wherein film-forming comprises exposing the preform to vapor of an organic solvent in the presence of air.
  33. 33. The method of claim 25, wherein film-forming comprises exposing the preform to vapor of an organic solvent substantially in the absence of air.
  34. 34. The method of claim 25, wherein film-forming comprises exposing to vapor of acetone, ethyl acetate, acrylonitrile, tetrahydrofuran, or another non-chlorinated organic solvent.
  35. 35. The method of claim 25, wherein the powder mixture further comprises particles which contain at least two out of the following three categories of substances: organic-solvent-soluble substances, water-soluble substances, and substantially-insoluble substances.
  36. 36. The method of claim 25, wherein manufacturing the preform comprises three dimensional printing.
  37. 37. The method of claim 25, wherein manufacturing the preform comprises manufacturing the preform containing empty macroscopic internal features having a cross-sectional dimension greater than approximately 100 micrometers.
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