Method and apparatus for engineered regenrative biostructures such as hydroxyapatite substrates for bone healing applications

• US 20030065400A1
• Filed: 04/12/2002
• Published: 04/03/2003
• Est. Priority Date: 04/12/2001
• Status: Active Grant

• Current Assignee: Theken Spine LLC (Orthofix Medical Inc.)
• Original Assignee: Therics Inc.
• Inventors: Wang, Chen-Chao, Gaylo, Christopher M., Yoo, Jaedeok, Liu, Qing, Pryor, Timothy J., Litwak, Alfred Anthony, West, Thomas George, Saini, Sunil, Beam, Heather Ann, Bradbury, Thomas J., Surprenant, Henry Leon, Chesmel, Kathleen D., Materna, Peter Albert, Monkhouse, Donald, Patterson, Jennifer
• Granted Patent: US 7,122,057 B2
• Time in Patent Office: Days
• US Class Current: 623/23.51
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2002/30032 differing in absorbability or resorbability, i.e. in absorption or resorption time
• CPC Class Codes: A61F 2002/30059 differing in bone mineralization, e.g. made from both mineralized and demineralized adjacent parts
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30225 Flat cylinders, i.e. discs
• CPC Class Codes: A61F 2002/30261 parallelepipedal
• CPC Class Codes: A61F 2002/30593 hollow
• CPC Class Codes: A61F 2002/30971 Laminates, i.e. layered products
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2230/0069 cylindrical
• CPC Class Codes: A61F 2230/0082 parallelepipedal
• CPC Class Codes: A61F 2250/0031 made from both resorbable and non-resorbable prosthetic parts, e.g. adjacent parts
• CPC Class Codes: A61F 2310/00293 containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: B33Y 30/00 Apparatus for additive manufacturing; Details thereof or accessories therefor
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing
• CPC Class Codes: C04B 2111/00181 : Mixtures specially adapted for three-dimensional printing (3DP), stereo-lithography or prototyping
• CPC Class Codes: C04B 2111/00836 : for medical or dental applications
• CPC Class Codes: C04B 2235/3212 : Calcium phosphates, e.g. hydroxyapatite
• CPC Class Codes: C04B 2235/447 : Phosphates or phosphites calcium phosphates C04B2235/3212, e.g. orthophosphate, hypophosphite
• CPC Class Codes: C04B 2235/5436 : micrometer sized, i.e. from 1 to 100 micron
• CPC Class Codes: C04B 2235/6026 : Computer aided shaping, e.g. rapid prototyping
• CPC Class Codes: C04B 2235/616 : Liquid infiltration of green bodies or pre-forms
• CPC Class Codes: C04B 2235/6567 : Treatment time
• CPC Class Codes: C04B 2235/80 : Phases present in the sintered or melt-cast ceramic products other than the main phase
• CPC Class Codes: C04B 2235/96 : Properties of ceramic products, e.g. mechanical properties such as strength, toughness, wear resistance
• CPC Class Codes: C04B 28/34 : containing cold phosphate binders
• CPC Class Codes: C04B 35/00 : Shaped ceramic products characterised by their composition porous ceramic products C04B38/00; ceramic articles characterised by particular shape, see the relevant classes, e.g. linings for casting ladles, tundishes, cups or the like B22D41/02; ceramic substrates for microelectronic semi-conductors H01L23/15; Ceramics compositions containing free metal bonded to carbides, diamond, oxides, borides, nitrides, silicides, e.g. cermets, or other metal compounds, e.g. oxynitrides or sulfides other than as macroscopic reinforcing agents C22C; shaping of ceramics B28B; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products chemical preparation of powders of inorganic compounds C01; infiltration of sintered ceramic preforms with molten metal C04B41/51
• CPC Class Codes: C04B 35/447 : based on phosphates , e.g. hydroxyapatite
• CPC Class Codes: C04B 35/634 : Polymers C04B35/636 takes precedence
• CPC Class Codes: C04B 35/638 : Removal thereof
• CPC Class Codes: C04B 38/0054 : the pores being microsized or nanosized
• CPC Class Codes: C04B 38/0074 : expressed as porosity percentage
• CPC Class Codes: C04B 38/06 : by burning-out added substances by burning natural expanding materials or by sublimating or melting out added substances

Abstract

An engineered regenerative biostructure (erb) for implantation into a human body as a bone substitute, which includes an internal microstructure, mesostructure and/or macrostructure to provide improved bone in-growth, and methods for making the erb. Under one aspect of the invention, the biostructure has resorbable and nonresorbable regions. Under another aspect of the invention, the biostructure is constructed of hydroxyapatite, tricalcium phosphate and/or demineralized bone. Under yet another aspect of the invention, the porous biostructure is partially or fully infused with a resorbable, nonresorbable or dissolvable material.

Claims

1. An engineered osteoconductive or osteoinductive biostructure comprising;

interconnected particles forming a matrix having at least one of a porous portion, the matrix having an engineered microstructure, mesostructure and macrostructure wherein the microstructure, the mesostructure and the macrostructure define the porous portion of the matrix.

2. The engineered regenerative biostructure of claim 1 wherein the microstructure has a median pore size between 10 to 15 microns.

3. The engineered osteoconductive or osteoinductive biostructure of claim 1 further including a bimodal pore size distribution, wherein a first peak of the bimodal pore-sized distribution represents the microstructure and a second peak of the -bimodal pore-size distribution represents the mesostructure.

4. The engineered osteoconductive or osteoinductive biostructure of claim 1 wherein the macrostructure has a cross-sectional dimension greater than 1 mm.

5. The engineered osteoconductive or osteoinductive biostructure of claim 1 wherein the matrix comprises demineralized bone particles and further comprising a binder substance interconnecting the particles of the matrix.

6. The engineered osteoconductive or osteoinductive biostructure of claim 5 further including a material infused into at least one of the porous portions of the biostructure.

7. The engineered osteoconductive or osteoinductive biostructure of claim 6 wherein the infused material is fibrin.

8. The engineered osteoconductive or osteoinductive biostructure of claim 6 wherein the infused material is a bioactive substance.

9. The engineered osteoconductive or osteoinductive biostructure of claim 5 wherein the binder substance is a collagen.

10. The engineered osteoconductive or osteoinductive biostructure of claim 5 wherein the biostructure is a bone substitute.

11. The engineered osteoconductive or osteoinductive biostructure of claim 1 wherein the matrix comprises particles selected from the group consisting of calcium phosphates, hydroxyapatite, tricalcium phosphate, demineralized bone, calcium salts, bone powder, organic bone, dental tooth enamel, aragonite, calcite, nacre, graphite, pyrolytic carbon, bioceramic and mixtures thereof.

12. The engineered osteoconductive or osteoinductive biostructure of claim 1 wherein the matrix comprises particles sintered together and further includes an infused material infused into at least one of the porous portions of the matrix.

13. A biostructure comprising a plurality of particles joined directly to each other, wherein space within the biostructure not occupied by the particles comprises pores, wherein the pores have a pore size distribution, and wherein the pore size distribution is unimodal within the interval 2 microns to 50 microns and has a median pore size of between 10 and 15 microns.

14. A biostructure comprising a plurality of particles joined together, the particles having an average particle diameter, and also comprising at least one of a mesostructure consisting of a first layer of inter-connected particles and a second adjacent layer of inter-connected particles defining a region of increased porosity there between, wherein the mesostructures have a shortest dimension whose smallest value is at least one particle diameters and less than 20 particle diameters, and have a longest dimension measured along a path, which may be irregular, from a first end to a second end, which is at least 10 times the shortest dimension, wherein the first end and the second end of the path may each be a dead end within the biostructure or an external surface of the biostructure or a branch point.

15. The biostructure of claim 14 wherein the shortest dimension of the -mesostructure is approximately 50 microns to 100 microns.

16. The biostructure of claim 14 wherein the mesostructure has a -packing density that is greater than zero.

17. The biostructure of claim 14 wherein the biostructure has mesostructures in some regions and no mesostructures in other regions.

18. The biostructure of claim 14 wherein the biostructure further comprises macrostructures, wherein the macrostructures are 1 mm or more in their minimum cross-sectional dimension.

19. A biostructure comprising a plurality of particles joined directly to each other, wherein space within the biostructure not occupied by the particles comprises pores, wherein the pores have a pore size distribution, and wherein the pore size distribution is bimodal in an interval between 2 microns and 200 microns and has a peak in the pore size distribution at between 10 and 15 microns and another peak in the pore size distribution larger than 25 microns.

20. The biostructure of claim 19 further including at least one of a macrostructure wherein the macrostructure has a smallest cross-sectional dimension of at least 1 mm.

21. The biostructure of claim 20 wherein the macrostructure has a cross-sectional area that is substantially constant.

22. The biostructure of claim 20 wherein at least one of a macrostructures intersects at least one of a second macrostructure.

23. The biostructure of claim 20 wherein three macrostructures intersect each other at a common location.

24. The biostructure of claim 19 wherein the particles are made of hydroxyapatite.

25. The biostructure of claim 19 wherein the particles comprise tricalcium phosphate or other calcium phosphate or other compound containing calcium and phosphorus.

26. The biostructure of claim 19, wherein the biostructure is a synthetic bone implant.

27. The biostructure of claim 19, wherein the biostructure is manufactured by three-dimensional printing.

28. A bone augmentation or tissue scaffold biostructure, comprising:

bone particles; and

at least one binder substance connecting the particles in a three-dimensional matrix, wherein the matrix includes microstructure, mesostructure and/or macrostructure, wherein the microstructure, mesostructure and/or macrostructure has one or more of a nonuniform cross-section, non-straight path, or branching.

29. The bone augmentation or tissue scaffold biostructure of claim 28 wherein the biostructure has a porosity greater than 40%.

30. The bone augmentation or tissue scaffold biostructure of claim 28, wherein the bone particles comprise one or more of fully demineralized, partially demineralized and superficially demineralized bone particles, and optionally nondemineralized bone particles.

31. The bone augmentation or tissue scaffold biostructure of claim 28, wherein the bone particles further comprise one or more substances selected from the group consisting of calcium phosphates, tricalcium phosphate, hydroxyapatite calcium salts, bone powder, demineralized bone powder, organic bone, dental tooth enamel, aragonite, calcite, nacre, graphite, pyrolytic carbon, Bioglass.RTM., bioceramic, and mixtures thereof.

32. The bone augmentation or tissue scaffold biostructure of claim 28, wherein the particles and the binder substance together leave some unoccupied space not occupied by either the particles or the binder substance, and further comprising, in at least some of the unoccupied space, a second substance.

33. The bone augmentation or tissue scaffold biostructure of claim 32, wherein the second substance is a bioactive substance.

34. The bone augmentation or tissue scaffold biostructure of claim 32 wherein the second substance is fibrin or a polymer.

35. The bone augmentation or tissue scaffold biostructure of claim 32 wherein the binder substance is collagen, and the second substance is fibrin.

36. The bone augmentation or tissue scaffold biostructure of claim 32 wherein the particles and the binder substance and the second substance together leave some further unoccupied space not occupied by any of those substances, and further comprising, in at least some of the further unoccupied space, a third substance.

37. The bone augmentation or tissue scaffold biostructure of claim 36, wherein the third substance is a bioactive substance.

38. The bone augmentation or tissue scaffold biostructure of claim 28 wherein the biostructure is a bone substitute for bone selected from the group consisting of the ethmoid, frontal, nasal, occipital, parietal, temporal, mandible, maxilla, zygomatic, cervical vertebra, thoracic vertebra, lumbar vertebra, sacrum, rib, sternum, clavicle, scapula, humerus, radius, ulna, carpal bones, metacarpal bones, phalanges, ilium, ischium, pubis, femur, tibia, fibula, patella, calcaneus tarsal and metatarsal bones and condyle.

39. A method of manufacturing an engineered regenerative biostructure, comprising:

depositing a layer of particles;

dispensing onto the layer of particles in selected places at least one binder substance;

repeating the above as many times as needed; and

removing unbound particles from the biostructure,

wherein an amount and pattern of binder substance dispensed onto the particles is selected so as to partially but not completely bind adjacent lines and layers to each other such that a microstructure, mesostructure and/or macrostructure is selectively designed into the biostructure.

40. The method of claim 39 wherein the binder substance has a decomposition temperature and wherein the binder substance decomposes into decomposition products which are gaseous at decomposition temperature and atmospheric pressure.

41. The method of claim 40 further comprising decomposing the binder substance.

42. The method of claim 39 wherein the particles comprise particles of demineralized bone matrix mixed together with particles of hydroxyapatite or tricalcium phosphate.

43. The method of claim 42 wherein the binder substance comprises collagen.

44. The method of claim 43 wherein the collagen is dissolved in ethanol/water or water.

45. The method of claim 39 wherein the particles contain particles of the binder substance and the dispensed liquid is a solvent for the binder substance.

46. The method of claim 39 wherein the particles comprise particles of demineralized bone that is coacervated with at least one binder substance.

47. The method of claim 46 wherein the binder substance is collagen or collagen derivatives.

48. The method of claim 39 wherein the particles comprise osteoinductive particles and also particles of a water-soluble substance, wherein the binder liquid further insoluble in water but soluble in another substance, wherein the water-soluble substance is dissolved out of the biostructure.

49. The method of claim 48 wherein the water-soluble substance is a salt or a sugar.

50. The method of claim 49 wherein at different layers the proportion of water-soluble substance in the powder is different.

51. The method of claim 39 further including sterilizing the biostructure.

52. The method of claim 39 further including, coacervating the particles with a coating of a binder substance.

53. The method of claim 52 wherein the coacervating process includes lyophilization.

54. The method of claim 39 wherein the dispensing of the liquid comprises dispensing differing amounts of one binder liquid or dispensing different binder liquids in different places in the biostructure.

55. The method of claim 39 wherein the depositing powder comprises depositing powder of varying composition in preselected places in the biostructure.

56. A bone augmentation or tissue scaffold biostructure made by the method of claim 39.

57. A biostructure comprising particles joined together to form a porous matrix comprising;

a first suspension of particles deposited in selected regions;

a second suspension of particles selectively deposited in locations other that the first suspension in the region; and

at least one of a binder material binding the first and the second suspension of particles into a porous matrix, wherein particles of the first suspension are joined directly to particles of the second suspension in predetermined places. particles of the first suspension and the particles of the second suspension in a porous matrix

58. The biostructure of claim 57 wherein the first suspension of particles is non-resorbable by the human body and the second suspension of particles is resorbable by the human body.

59. The biostructure of claim 58, wherein the first particles consist of hydroxyapatite and the second particles consist of tricalcium phosphate or another resorbable calcium-phosphorus compound.

60. The biostructure of claim 57, wherein the biostructure is a bone substitute.

61. The biostructure of claim 57, further comprising an interpenetrating material that fully or partially occupies a porous region of the matrix.

62. The biostructure of claim 61, wherein the interpenetrating material is a polymer.

63. The biostructure of claim 62, wherein the polymer is nonresorbable.

64. The biostructure of claim 62, wherein the polymer is resorbable.

65. The biostructure of claim 57 further comprising one or more bioactive substances.

66. The biostructure of claim 57, wherein the binder substance or binder substances are not excessively soluble in water or isopropanol.

67. The biostructure of claim 57, wherein the binder substance or one of the binder substances is polyacrylic acid.

68. A method of depositing a layer of powder, comprising:

selecting a pattern of dispensing for a first and a second suspension of particles onto a layer on a build bed;

continuously dispensing the first suspension of particles into the first selected pattern or region of the layer;

continuously dispensing the second suspension of particles into the second selected pattern or region of the layer wherein the second suspension is deposited in a region of the layer not occupied by the first suspension; and

selectively dispensing a binder into the layer comprising the first and the second suspension wherein the binder binds the particles together to form a porous matrix.

69. The method of claim 68, further comprising using a three-way valve to vary a composition of either the first or the second suspension.

70. The method of claim 68, comprising using two two-way valves to vary dispensing of a composition from either the first or the second suspension.

71. The method of claim 68 wherein the first suspension is dispensed by a first dispenser and the second suspension is dispensed by a second dispenser, wherein each dispenser is aimed at a common location in the plane of the build bed, each dispenser dispensing at particular times so as to produce the selected pattern.

72. The method of claim 71, wherein each dispenser is a piezoelectric drop-on-demand dispenser.

73. The method of claim 71, wherein each dispenser is a microvalve-based dispenser.

74. The method of claim 73, wherein the microvalve operates by opening for short discrete intervals.

75. The method of claim 73, wherein the microvalve operates by opening and remaining open for substantial intervals of time.

76. The method of claim 68 wherein the dispensing is performed by a nozzle or array of dispensers, and more than one such nozzle or array of dispensers can be operated simultaneously, and may be separately instructed.

77. The method of claim 68 wherein the suspension comprises a carrier liquid, and further comprising:

dispensing onto the layer in predetermined printing locations a binder liquid comprising one or more binder substances which are not excessively soluble in the carrier liquid;

repeating the above steps as many times as needed;

removing powder which has not received binder liquid;

heating the biostructure to a sufficient temperature for a sufficient time to decompose the binder substance(s), and sintering the particles together by heating the biostructure.

78. The method of claim 68, further comprising infusing an interpenetrating material into the porous matrix.

79. The method of claim 78, wherein the interpenetrating material is a polymer.

80. The method of claim 78, further comprising depositing one or more bioactive agents into empty spaces in the biostructure.

81. An biostructure manufactured by the method of claim 68.

82. Apparatus for depositing a layer of powder onto a build bed, comprising:

two or more suspension reservoirs;

means for connecting the two or more suspension reservoirs to a common nozzle;

means for switching among the two or more suspension reservoirs at predetermined times so that at any given time only one suspension reservoir is connected to the nozzle; and

a motion control system for moving the nozzle relative to the build bed.

83. The apparatus of claim 82, wherein the switching means comprises a three-way valve.

84. The apparatus of claim 82, wherein the switching means comprises two two-way valves.

85. Apparatus for depositing a layer of powder onto a build bed, comprising:

two or more suspension dispensers, each aimed at the build bed;

means for activating individual suspension dispensers at predetermined times; and

a motion control system for moving the dispensers relative to the build bed.

86. The apparatus of claim 85 wherein the two or more suspension dispensers are each aimed at different points on the plane of the build bed.

87. The apparatus of claim 85 wherein the motion control system comprises a fast axis direction of motion, and the two or more suspension dispensers are all mounted along a line that is parallel to the fast axis.

88. A biostructure comprising a porous three-dimensional matrix and interpenetrant network interlocking with the matrix, wherein the interpenetrant network contains an interpenetrating material that is water-soluble and is solid or semi-solid at room temperature.

89. The biostructure of claim 88 wherein the biostructure is a tissue scaffold.

90. The biostructure of claim 88 wherein the biostructure is a bone substitute.

91. The biostructure of claim 88 wherein the biostructure has an overall external surface, and the overall external surface of the biostructure is shaped to mate with a corresponding surface of natural bone in a patient'"'"'s body.

92. The biostructure of claim 88 wherein the interpenetrating material is soluble in water to a solubility of greater than one part in 10,000 at body temperature.

93. The biostructure of claim 92 wherein the interpenetrating material is soluble in water to a solubility of greater than one part in 1,000 at body temperature.

94. The biostructure of claim 92 wherein the interpenetrating material is soluble in water to a solubility of greater than one part in 100 at body temperature.

95. The biostructure of claim 92, wherein the interpenetrating material is soluble in water to a solubility of greater than one part in 10 at body temperature.

96. The biostructure of claim 88 wherein the wherein th e interpenetrating material completely occupies the interpenetrant network.

97. The biostructure of claim 88 wherein the wherein the interpenetrating material partially occupies the interpenetrant network.

98. The biostructure of claim 88 wherein the interpenetrating material has a melting temperature and a decomposition temperature, and the melting temperature is less than the decomposition temperature.

99. The biostructure of claim 98 wherein at some temperature less than the decomposition temperature, the melted interpenetrating material has a viscosity less than 20 cP.

100. The biostructure of claim 88 wherein the interpenetrating material is a sugar alcohol or an alcohol or a sugar or a polymer or a salt or a mixture of substances which are members of one or more of those categories.

101. The biostructure of claim 88 wherein the interpenetrating material is selected from the group consisting of mannitol, sorbitol, xylitol, lactose, fructose, sucrose, maltose, dextrose, other sugars, polyethylene glycol, polyethylene oxide, polypropylene oxide, polyvinyl alcohol, and mixtures thereof.

102. The biostructure of claim 88 wherein the interpenetrating material comprises one or more bioactive or beneficial substances.

103. The biostructure of claim 102 wherein the one or more bioactive or beneficial substances comprises one or more substances selected from the group consisting of antibiotics, Active Pharmaceutical Ingredients, anesthetics, anti-inflammatory substances, growth promoting substances, hormones, peptides, bone morphogenic proteins, cells, cell fragments, cellular material, proteins, growth factors, other biological or inert materials, hormones and peptides.

104. The biostructure of claim 88 wherein the interpenetrating material further comprises micelles or suspended particles of another substance.

105. The biostructure of claim 88 wherein the biostructure further comprises one or more regions that is infused with a second substance different from the interpenetrating material or are not infused at all.

106. The biostructure of claim 105, wherein the biostructure has an overall external surface, and the region infused by the water-soluble interpenetrating material occupies the interpenetrant network in a layer which follows the shape of at least a portion of the overall external surface.

107. The biostructure of claim 105 wherein the second substance is dissolvable or resorbable or nonresorbable.

108. The biostructure of claim 88 wherein the porous matrix is in the form of particles joined to other particles by neck regions.

109. The biostructure of claim 88 wherein the matrix material is resorbable.

110. The biostructure of claim 88 wherein the matrix material is nonresorbable.

111. The biostructure of claim 88 wherein the matrix material is hydroxyapatite or is tricalcium phosphate or another resorbable substance containing calcium and phosphorus.

112. The biostructure of claim 88 wherein the matrix material is a resorbable polymer or a non-resorbable polymer.

113. The biostructure of claim 88 wherein the matrix material is a comb polymer.

114. The biostructure of claim 88 wherein the biostructure is manufactured by processes which include three-dimensional printing.

115. The biostructure of claim 88 wherein the biostructure is manufactured by processes which include partial sintering.

116. The biostructure of claim 88, wherein the biostructure is manufactured by:

manufacturing the matrix-material network;

infusing the matrix-material network with a solution of water-soluble substance dissolved in a solvent; and

allowing or causing the water-soluble substance to come out of solution so as to occupy at least some of the space not occupied by the matrix-material network.

117. A method of manufacturing a biostructure, comprising:

creating a porous matrix by three-dimensional printing, and infusing into at least portions of the porous matrix a water-soluble interpenetrating material.

118. The method of claim 117 wherein infusing the water-soluble material is performed by melting the material and infusing the melted material into the biostructure.

119. The method of claim 117 wherein infusing the water-soluble material is performed by dissolving the material in a solvent to form a solution, immersing the biostructure in the solution, and causing the material to come out of solution.

120. The method of claim 118 wherein the coming out of solution is caused by evaporation of the solvent or change in temperature of the solution.

121. A biostructure comprising particles joined together to form a porous matrix comprising;

a plurality of layers, the layers comprising particles; and

at least one of a binder material binding the particles into a porous matrix, wherein predetermined places, the particles have a first composition, and, in other predetermined places, the particles have a second composition which can be chemically derived from the first composition.

122. The biostructure of claim 121 wherein the first composition is hydroxyapatite and the second composition is tricalcium phosphate.

123. The biostructure of claim 121 wherein the first composition is tricalcium phosphate and the second composition is hydroxyapatite.

124. The biostructure of claim 121 wherein the biostructure is a bone substitute.

125. The biostructure of claim 121 wherein the powder particles joined to each other form a first network, and the space not occupied by the powder particles joined to each other forms a second network, which interlocks with the first network.

126. The biostructure of claim 124, further comprising an interpenetrating material that fully or partially occupies the second network.

127. The biostructure of claim 125, wherein the interpenetrating material is a polymer.

128. The biostructure of claim 127, wherein the polymer is nonresorbable.

129. The biostructure of claim 127, wherein the polymer is resorbable.

130. The biostructure of claim 121 further comprising one or more bioactive substances.

131. The biostructure of claim 125 wherein the inter-penetrating material is dissolvable.

132. A method of manufacturing a biostructure comprising particles joined together, comprising:

depositing a layer of powder which may be of uniform composition;

dispensing onto the layer of powder in predetermined places a liquid containing a reactant suitable to chemically react with the powder and transform it into a different substance;

repeating the above steps as many times as needed;

harvesting and de-dusting to produce a biostructure; and

heating the biostructure sufficiently to cause the powder which is in contact with the reactant to transform into a second solid substance.

133. The method of claim 132, further comprising heating to a sufficient temperature for sufficient time to partially sinter the biostructure.

134. The method of claim 132 wherein the first substance is hydroxyapatite and the second substance is tricalcium phosphate and the reactant is a substance containing phosphorus.

135. The method of claim 132 wherein the reactant is selected from the group consisting of phosphoric acid, ammonium phosphate, organic phosphates, and salts which are phosphates.

136. The method of claim 132 wherein the first substance is tricalcium phosphate and the second substance is hydroxyapatite and the reactant is a substance containing calcium.

137. The method of claim 132 wherein the dispensing is performed by a microvalve dispenser.

138. The method of claim 132 wherein the dispensing is performed by a piezoelectric drop-on-demand dispenser.

139. The method of claim 132 wherein the dispensing is performed by a nozzle or array of dispensers, and more than one such nozzle or array of dispensers can be operated simultaneously, and may be separately instructed.

140. The method of claim 132 wherein sintering is performed according to a sintering protocol which can simultaneously achieve all of the following:

partial sintering of hydroxyapatite particles to themselves;

partial sintering of tricalcium phosphate particles to themselves; and

partial sintering of hydroxyapatite particles and tricalcium phosphate particles to each other.

141. The method of claim 132, further comprising infusing an interpenetrating material into empty spaces in the biostructure.

142. The method of claim 141, wherein the interpenetrating material is a polymer.

143. The method of claim 132, further comprising depositing one or more bioactive agents into empty spaces in the biostructure.

144. A biostructure manufactured by the method of claim 132.

145. A biostructure, comprising a matrix-material network, having matrix-material network surfaces;

and in at least a first region of the biostructure, on the matrix-material network surfaces, one or more interpenetrant materials, such that the matrix material and the interpenetrant material together form a matrix-material-plus-interpenetrant network, wherein space not occupied by the matrix-material-plus-interpenetrant network forms a non-(matrix-material-plus-interpenetrant) network which interlocks with the matrix-material-plus-interpenetrant network, wherein the biostructure is manufactured by;

manufacturing the matrix-material network by three-dimensional printing;

infusing the matrix-material network with a solution comprising a polymer dissolved in a solvent;

draining solution which can be drained; and

allowing or causing the solvent to evaporate.

146. The biostructure of claim 145 wherein the manufacturing of the matrix-material network further includes, after three-dimensional printing, partially sintering the matrix-material network.

147. The biostructure of claim 145, wherein the manufacturing further includes infusing monomer into the non-(matrix-material-plus-interpenetrant) network causing the monomer remaining in the (matrix-material-plus-interpenetrant) matrix-material network to polymerize.

148. The biomedical biostructure of claim 145 wherein the matrix-material network is manufactured by three-dimensional printing.

149. A method of manufacturing a biomedical biostructure, comprising:

creating, by three dimensional printing, a matrix-material network, with the space not occupied by the matrix-material network forming a non-matrix-material network which interlocks with the matrix-material network; and

introducing into the non-matrix-material network a liquid containing interpenetrating material;

removing some of the liquid; and

causing or allowing at least some of the remaining liquid to harden.

150. The method of claim 149 wherein the liquid is a solution comprising interpenetrating material in a solvent, the solvent being capable of evaporating to deposit interpenetrating material.

151. The method of claim 149 wherein the liquid is melted interpenetrating material.

152. The method of claim 149 wherein the liquid is a monomer capable of hardening by polymerization.

153. The method of claim 149 wherein the biostructure has multiple regions, and further comprising introducing different liquids into different regions or the same liquid different numbers of times into different regions.