Porous hydrophilic composite materials for use in promoting bone growth - Patents.com

Abstract

A porous hydrophilic composite material for use in bone growth is disclosed along with a method for its preparation. The composite material includes a porous biodegradable polymer matrix and nano-sized calcium phosphate (CaP) uniformly dispersed throughout the polymer matrix. The CaP has a particle size ranging from about 180 to about 380 nm. 2 / g range of specific surface area.

Description

[Technical field]

[0001] The present invention generally relates to a porous hydrophilic composite material that can act as a scaffold for bone cell growth, and a method for preparing the same. The composite material includes nano-sized calcium phosphate (CaP) and a biodegradable polymer. The composite material can be applied to a surface, such as an implant surface. The thickness of the composite layer on the implant surface can be controlled. [Background technology]

[0002] In the medical field, there are many situations where it is necessary to help the human body to build new bone. Small fractures are usually repaired without guidance if the ends of the fracture are located close enough to each other. Bone tissue can bridge gaps of a few millimeters, but bone loss of more than 5-10 mm results in so-called critical size defects that require procedures for repair. Compound fractures can damage bone tissue to such an extent that normal repair is insufficient. Tumors that destroy large parts of the bone tissue can make it impossible for the body itself to repair the injury. Another example is the so-called sinus lift, where the natural bone is too thin to support a dental implant and the bone tissue must be strengthened.

[0003] The insertion of a bone scaffold is a common procedure that helps the body generate new bone. Bone scaffold materials have a structure and composition that induces bone formation when implanted into the body, and act as a growth substrate for bone cells.

[0004] The bone scaffold can be of biological origin, for example, obtained from the patient's own bone (autograft) or from another donor (allograft) before surgery. The bone scaffold can also be manufactured from animals, such as bovine bone (xenograft). Autografts and allografts have a good effect on bone tissue growth, but require surgery for bone removal, and handling and storage of the graft is complicated. Xenografts have the advantage of not requiring any surgery on the patient to obtain, but require rigorous cleaning and sterilization procedures due to the risk of infection.

[0005] Synthetic bone scaffolds have also been proposed. The main advantage of synthetic scaffolds compared to biological bone grafts is that they can be produced in large quantities and with controlled specifications. Synthetic bone scaffolds can be in the form of powders such as hydroxyapatite (HA) or tricalcium phosphate. Powder-based products are useful for bone tissue restoration but are less suitable for load-bearing applications. Another type of bone scaffold is the rigid type, which usually consists of porous HA or tricalcium phosphate sintered at high temperatures. The main advantage of rigid bone scaffold products is their morphological stability and porosity upon implantation, which increases the surface area available for new bone cells to grow. One of the disadvantages is the brittleness of the structure. Rigid bone scaffolds usually do not contain flexible substances such as polymers, which can dissipate forces on the material and prevent the formation of cracks.

[0006] One way to reduce the brittle nature of rigid inorganic scaffolds is to incorporate polymers within the structure. Polymer / inorganic composites consist of a biodegradable polymer and an inorganic material with bone regenerative properties, such as HA. The polymer makes the composite elastic and crack-resistant, while the inorganic material induces endogenous bone formation.

[0007] In addition to the porosity of the bone scaffold, the crystal size of the calcium phosphate is also important for stimulating endogenous bone growth. HA, with the chemical formula Ca5(PO4)3OH, is a mineral that is very similar to the inorganic calcium phosphate found in natural bone. For certain biomaterial applications, it is highly desirable to use nanosized HA, with particle sizes similar to those found in human bone, i.e., 1-100 nm in length. Natural bone consists of rod-shaped calcium phosphate crystals, 20-40 nm in length, 2 nm in thickness, and 2-4 nm in width, surrounded by a collagen network (HA Lowenstam and S. Weiner, On biomineralization, Oxford University Press, New York, 1989).

[0008] It is generally believed that the bioactivity of HA is improved when the HA crystals are similar in size and shape to the crystals that form in the human body. Nanocrystalline HA can stimulate bone remodeling because the body recognizes nanosized HA as part of its own bone tissue and starts to grow new bone around the foreign material. In implants, coating with nanosized HA significantly increases bone cell activity compared to microsized HA. In polymer / HA composites, the bioactivity and strength are greatly improved with nanosized HA (J.Wei, Y.Li and K.Lau, Composites part B: engineering 2007, vol. 38, pp. 301-305; H.Ramay and M.Zhang, Biomaterials, 2003, vol. 24, pp. 3293-3302).

[0009] In the literature, the production of several bioactive and biodegradable porous scaffolds made from polymers and ceramic materials such as polycaprolactone and hydroxyapatite has been described. For example, composites of porous PCL and HA with different percentages of HA can be produced by selective laser sintering. The researchers found that with increasing amounts of HA, the compressive stiffness increases and the porosity decreases (K. Rezwan et al., Biomaterials 2006, vol. 27(18): 3413-31). Another example is the production of porous PCL / HA composites by precision extrusion, which produces scaffolds with different porosities and pore sizes. Osteoblasts have been cultivated and shown to migrate and proliferate for these scaffolds (L. Shor et al., Biomaterials 28, vol. 35, December 2007, pp. 5291-5297).

[0010] US 2010 / 226956 describes moldable composites made from polycaprolactone, hydroxyapatite and various bioabsorbable plasticizers. The moldability of the composite is controlled by the amount and type of plasticizer used. When the composite is implanted in the body, the plasticizer is absorbed, leaving a porous structure. The composite is made by melt mixing. However, it has been found that hydrophilic HA cannot be completely dispersed in the hydrophobic polymer during melt mixing, resulting in a composite containing mostly pure polymer, making the entire composite hydrophobic (i.e., water contact angle >90°).

[0011] China Patent Publication No. 102008752 discloses a method for forming a nano-hydroxyapatite coating on the surface of a porous biphasic calcium phosphate bioscaffold using chemical precipitation. The result is a porous biphasic calcium phosphate bioscaffold with a nano-hydroxyapatite coating. However, HA crystals are not dispersed in the polymer matrix.

[0012] EP 3785743 presents various methods for producing porous polymer scaffolds with calcium phosphate inclusions, however the calcium phosphate used in the scaffolds is not nano-sized.

[0013] CN107823715 discloses a PCL / HA composite porous bone tissue engineering scaffold, characterized in that the scaffold is composed of polycaprolactone and hydroxyapatite. The content of hydroxyapatite is 0.5-50% on a mass percentage basis, with the remainder being polycaprolactone. The porosity is controlled by the use of pore-forming agents such as sodium carbonate, sodium bicarbonate and potassium carbonate, which are then removed by the use of strong acids such as hydrochloric acid, sulfuric acid or nitric acid, which dissolve the pore-forming compounds. The formation of carbon dioxide during dissolution creates pores and helps to create an interconnected porous structure. However, the acid used to dissolve the pore-forming agents will dissolve any HA that is not fully embedded and protected by the polymer matrix. The result is a polymer / HA composite with little or no HA on the polymer surface, which reduces its hydrophilicity and bioactivity for bone cell growth. Furthermore, since PCL begins to degrade at acidic pH, this method increases the risk of premature degradation of the PCL matrix.

[0014] US6165486 discloses compositions comprising HA, polycaprolactone (PCL) and copolymers of poly(lactic) acid and poly(glycolic) acid (PLGA), as well as the blends and shaping into bioceramics implants. Porosity is generated by adding NaCl as a pore-forming agent, which is removed with water. However, there is always a risk of having residual NaCl crystals present in the composite, which negatively impacts the in vivo performance. Weight loss curves for various composites stored in phosphate buffered saline (pH 7.4) at 37°C are shown in Figures 1 and 2 of US6165486. Since PCL and PLGA are expected to degrade very slowly in sterile PBS buffer at pH 7.4 in the absence of any enzymes, the observed weight loss could be attributed to the dissolution and weight loss of NaCl crystals added to generate porosity, which take more than 8 weeks to leach out of the structure.

[0015] ES 2 330 823 discloses a polymeric scaffold formed by thermally induced phase separation with deposition of hydroxyapatite, which consists of a polymer network with a thin coating of HA on the internal surfaces of the pores within the polymer network.

[0016] CN100546661 discloses a method for preparing an in situ pore-forming self-hardening calcium phosphate composite scaffold. The porous calcium phosphate scaffold is then filled with a polymer, which may then be crosslinked. The resulting product is a dense structure with low porosity and no open cells.

[0017] Bone scaffolds are often used together with load-bearing non-degradable structures such as spinal fusion cages. This approach is particularly useful when a larger volume of bone needs to be built around the implant. In the case of spinal fusion surgery, the interior of the spinal fusion cage can be wrapped with bone scaffold material to combine the high mechanical strength of the spinal cage with the osteostimulatory properties of the bone scaffold. However, this type of implant is difficult to handle and requires preparation of the implant with the bone scaffold on the site surface. Therefore, it would be of great benefit to have a scaffold that can be tailored for the implant. Summary of the Invention [Problem to be solved by the invention]

[0018] A first object of the present invention is to provide a porous hydrophilic composite material comprising nano-sized calcium phosphates such as amorphous calcium phosphate (ACP), beta-TCP, calcium deficient HA (CDHA) or hydroxyapatite (HA) and a biodegradable polymer, which acts as a scaffold for bone cell growth. Another object of the present invention is to provide a method for producing a layer of composite material on a surface, such as an implant surface, to form an osteoconductive coating on the implant. Yet another object of the present invention is to provide a method for producing a porous composite material in situ within the interstices of an implant or on the surface of an implant or within the pores of a porous metal lattice structure, whereby the geometry of the composite material can be controlled. Yet another object of the present invention is to allow for the control of the geometry by layer-by-layer deposition to produce highly ordered structures.

[0019] Other objects and advantages of the present invention will become apparent to the reader, and these objects and advantages are intended to be within the scope of the present invention. [Means for solving the problem]

[0020] In one aspect, a porous hydrophilic composite material is provided that can act as a scaffold for bone cell growth. The porous hydrophilic composite material comprises: (a) a porous biodegradable polymer matrix, and (b) Approximately 180~380m 2 Nanosized calcium phosphate (CaP) uniformly dispersed throughout the polymer matrix with a specific surface area in the range of 0.1 to 1.0 μm / g Includes. With the proviso that said composite material does not contain any copolymer of lactic acid and glycolic acid.

[0021] In another aspect, there is provided a scaffold for use in bone reconstruction comprising the porous hydrophilic composite material of the present invention and a substrate, such as an implant. The composite material may be present as a coating on the surface of the substrate, or the substrate may be completely or partially surrounded by the composite material.

[0022] In another aspect, there is provided a first method of preparing a porous hydrophilic composite material, the method comprising: (a) mixing a solution of a biodegradable polymer in a first solvent with nanosized calcium phosphate (CaP), preferably a dispersion of nanosized calcium phosphate (CaP) in a second solvent, until the CaP is uniformly distributed throughout the resulting mixture; (b) solidifying the mixture of step (a) to form a gel; and (c) removing the first and second solvents from the gel of step (b) by washing with a third solvent to leave a porous hydrophilic composite material containing nanosized CaP uniformly dispersed in a porous polymer matrix. A method of preparation is provided, comprising:

[0023] In another aspect, there is provided a second method of preparing a hydrophilic composite material for promoting bone growth, the method comprising: (a1) mixing a solution of a biodegradable polymer in a first solvent with nanosized calcium phosphate (CaP), preferably a dispersion of nanosized calcium phosphate (CaP) in a second solvent, until the CaP is uniformly distributed throughout the resulting mixture; (b1) solidifying the mixture of step (a) on a substrate to form a gel; and (c1) removing the first and second solvents from the gel of step (b) by solvent evaporation to leave a layer of porous hydrophilic composite material containing nanosized CaP dispersed throughout a porous polymer matrix on the surface. A method of preparation is provided, comprising:

[0024] In the method of the present invention, a dispersion of nanosized calcium phosphate (CaP) in a second solvent may be prepared by mixing a dispersion of a non-phosphate calcium salt, such as CaO, in a suitable solvent with an aqueous phosphoric acid solution.

[0025] In the method of the present invention, the first and second solvents may be the same or different, but are preferably the same. The third solvent used in the first method is different from the first and second solvents.

[0026] In another embodiment, the method of the present invention may further include the steps of (d) immersing the porous hydrophilic composite in a solution comprising a biocompatible organic polyol, (e) removing the porous hydrophilic composite from the solution, and (f) drying the porous hydrophilic composite to further enhance the hydrophilicity of the composite structure.

[0027] The CaP used in the above method is preferably about 180 to about 380 mM. 2 / g range of surface area.

[0028] In another aspect, there is provided a method for preparing nanosized CaP, said method comprising mixing a dispersion of a non-phosphate calcium salt in a suitable non-aqueous solvent with an aqueous phosphoric acid solution to form amorphous nanosized CaP, and optionally contacting the amorphous CaP with water to convert the amorphous CaP to HA or β-TCP.

[0029] The products of the processes of the present invention form a further aspect of the present invention. [Brief description of the drawings]

[0030] [Figure 1] FIG. 2 is a powder X-ray diffractogram of a nanocrystalline HA sample. [Diagram 2] FIG. 2 is a powder X-ray diffractogram of a nanosized amorphous HA sample. [Figure 3a] FIG. 1 is a schematic diagram of step 1 of composite material production. [Figure 3b] FIG. 1 is a schematic diagram of step 2 of composite material production. [Figure 4] Figures 1a) and 1b) of a porous composite material prepared according to Example 1d without nanosized HA after immersion in toluidine blue, and (b) of the same sample cut into two pieces showing the interior of the sample, and (c) of a porous composite material prepared according to Example 1c with nanosized HA after immersion in toluidine blue, and (d) of the same sample cut into two pieces showing the interior of the sample. [Diagram 5] FIG. 11 is a diagram of a spinal cage (left image) with a layer of composite material (right image) inside the implant, prepared according to Example 6. [Figure 6] Images of titanium lattices containing in situ formed CaP / PCL foams (a) and (b) before immersion in Alizarin Red, and images of different 3D printed titanium samples with various mesh sizes (c) after immersion in Alizarin Red. [Figure 7] A diagram of the method for producing a screw coated with a 1 mm composite layer (a) and a photograph of the composite coated screw (b). [Figure 8] Micro-CT images of a sham (a) after 6 weeks and a sham (b) with porous composite in place after 6 weeks placed on a rabbit calvaria. The site with the porous composite has grown completely with bone. [Figure 9] A Masson-Goldner stained slide of the sample shown in Figure 8b. [Figure 10]1 is a scanning electron microscope (SEM) image of the sample prepared in Example 1c. [Figure 11] 13 is an image of a pin array placed on foam according to Example 10. [Figure 12a] 1 is a photograph of the composite material of Example 1c after immersion in red dye for 30 minutes. [Figure 12b] 1 is a photograph of the composite material of Example 1c after glycerol treatment according to Example 11 and then immersion in red dye for 30 minutes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] Reference will now be made in detail to the presently preferred embodiments of the invention.

[0032] All references mentioned below are incorporated by reference in their entirety to the extent not inconsistent with this disclosure.

[0033] Ranges obtained by combining any of the lower limits with any of the upper limits of the ranges disclosed herein are also encompassed by the invention.

[0034] The present invention includes a porous hydrophilic composite material comprising (or consisting essentially of, or consisting only of) a matrix of nanosized calcium phosphate (CaP) and a biodegradable polymer. Due to the bioactive properties of the nanosized CaP particles, the high surface area of ​​the polymer / CaP composite and its hydrophilicity, the composite material can act as an excellent scaffold for bone cell growth.

[0035] CaP As used herein, nano-sized refers to particles having a longest dimension of 1 to 100 nm. Particles having a longest dimension of 1 to 50 nm, for example 5 to 40 nm or 10 to 20 nm, are preferred.

[0036] The particles may be of any shape, such as substantially spherical, hexagonal cross-section, or fibrous.

[0037] As used herein, CaP refers to any form of calcium phosphate, including but not limited to amorphous CaP (ACP), beta-tricalcium phosphate (β-TCP), tetracalcium phosphate (TTCP), hydroxyapatite (HA) or calcium-deficient HA (CDHA). Preferred forms of CaP include HA.

[0038] Amorphous calcium phosphate (ACP) is non-crystalline and can have various Ca / P ratios, with beta-tricalcium phosphate (β-TCP) having a Ca / P ratio of 1.5. The dissolution of calcium phosphate particles is greatly influenced by their structure and size. The absorption rate of calcium phosphate polymorphs in an acidic environment is ACP>β-TCP>TTCP>HA (SV Dorozhkin, Biomaterials vol. 31 (2010) pp. 1465-1485), and the dissolution and release of calcium and phosphorus in vivo can be controlled by the choice of CaP compound used.

[0039] CaP may be amorphous or crystalline. In the case of crystalline CaP, the term "nano-sized" refers to the size of the individual crystals, whereas in the case of amorphous CaP, it refers to the size of the individual particles. Nano-sized crystalline CaP may also be referred to as "nanocrystalline CaP."

[0040] When amorphous CaP with a Ca / P ratio of 5 / 3 is used in the composite material of the present invention, this amorphous CaP may be converted to crystalline HA when exposed to body fluids in vivo. Since amorphous CaP has lower mechanical strength compared to crystalline HA, this effect can be used to generate composite materials with increased strength after implantation. Furthermore, since the conversion of ACP to HA is thermodynamically favorable, this conversion accelerates the infiltration of body fluids, which also increases the adhesive strength between the composite material and the surrounding bone.

[0041] Nanosized CaP is usually commercially available in powder form or can be synthesized using methods known in the art, for example, methods for synthesizing nanosized CaP are disclosed in WO 2005 / 123579 and US 2010 / 0226956.

[0042] Nano-sized crystalline CaP can be synthesized by a method that involves mixing (i) a dispersion of a non-phosphate calcium salt in water or a non-aqueous solvent with (ii) an aqueous solution of phosphoric acid. This results in a dispersion of nanocrystalline CaP that can be used directly in the first or second methods to form the composite materials discussed below.

[0043] By using a non-aqueous dispersion of a non-calcium phosphate salt instead of an aqueous dispersion, optionally with a further ageing step, the method can be used to produce HA or other types of calcium phosphates such as ACP, beta-TCP or CDHA.

[0044] The ratio of non-phosphate calcium salts to phosphate can affect the CaP compound formed.

[0045] To obtain CaP with a high surface area, the non-calcium phosphate salt should have low solubility in water or the solvent used to form the non-aqueous dispersion. Preferred non-calcium phosphate salts are calcium oxide and calcium hydroxide.

[0046] Thus, in another aspect, the present invention provides a method for preparing amorphous nanosized CaP, said method comprising mixing a dispersion of a non-phosphate calcium salt in a suitable non-aqueous solvent with an aqueous phosphoric acid solution to form amorphous nanosized CaP. Suitable non-aqueous solvents for use in this method include glycerol and ethylene glycol.

[0047] Preferably, the non-aqueous solvent is miscible with water. Preferably, the non-aqueous solvent is miscible with acetone or another volatile polar solvent, allowing the acetone or another volatile polar solvent to be easily removed by washing with such a non-aqueous solvent.

[0048] If desired, the CaP formed in this manner can then be processed by contacting it with water to convert it into a different form of CaP. For example, when ethylene glycol or glycerol is used to form a dispersion of non-calcium phosphate salts other than water, ACP can be produced. The ACP can be aged by contacting with water at room temperature to produce HA, if desired. Alternatively, β-TCP can be produced by contacting with water at high temperature and pressure, such as in an autoclave. Autoclaving involves heating the powder in a sealed container (e.g., a stainless steel bomb) in the presence of water. This is done at high temperature (e.g., 180°C to 220°C), so the pressure will be greater than 1 atmosphere, typically 5 to 15 atmospheres. The particle size and surface area of ​​the CaP produced can be controlled by controlling the temperature and duration of contact with water.

[0049] The specific surface area of ​​CaP is about 180 to about 380 m when measured by the BET method. 2 / g (S. Brunauer, PH Emmet, E. Teller, J. Am. Chem. Soc. 1938, Vol. 60, pp. 309-319). Preferably, the specific surface area of ​​CaP is in the range of about 200 to about 350 m 2 / g, more preferably about 200 to about 250 m 2 / g range. Amorphous nanosized CaP tends to have a larger surface area than nanocrystalline CaP.

[0050] X-ray diffraction (XRD) may also be used to obtain a rough measurement of the surface area of ​​the CaP in the composite. For more precise measurements, a suitable solvent (e.g., acetone) can be used to dissolve the polymer from the composite, and the resulting surface area of ​​the CaP can be measured by the BET method.

[0051] polymer The polymers used in the composite material should be biodegradable in vivo, and preferably degrade over a period of about 3 months to about 3 years, for example about 6 months to about 2 years, preferably about 3 to about 12 months.

[0052] The polymers used in the composite material should also be biocompatible.

[0053] Biodegradable polymers can be synthetic or natural.Suitable biodegradable polymers include synthetic polyesters such as poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGL), poly(vinyl alcohol) (PVA), and natural polymers such as soluble collagen, hyaluronic acid, gelatin and chitosan.These polymers undergo hydrolysis in the human body to produce non-toxic degradation products (L. Nair and C. Laurencin, Progress in polymer science, 2007, vol. 32, pp. 762-798).

[0054] Biodegradable polymers may be water-soluble or water-insoluble, although water-insoluble polymers are preferred: polyesters such as PCL, PLA and PGL are water-insoluble, while poly(vinyl alcohol) (PVA), soluble collagen, hyaluronic acid, gelatin and chitosan are water-soluble.

[0055] The rate of biodegradation can be controlled by the choice of polymer: PCL, for example, generally degrades slower in vivo than PLA or PGA.

[0056] The polymer preferably used in the present invention is PCL. More preferably, PCL is the only polymer present in the composite. For example, the polymer matrix may consist of PCL. PLA and PGL degrade in vivo and produce acidic degradation products (lactic acid and glycolic acid, respectively), which may cause undesirable inflammatory reactions. In contrast, the in vivo degradation product of PCL (6-hydroxyhexanoic acid) is less acidic and therefore less likely to cause undesirable inflammatory reactions. The pKa of lactic acid is 3.86, while the pKa of 6-hydroxyhexanoic acid is 4.75.

[0057] Preferably, the polymer matrix is ​​formed from a single polymer, although mixtures may also be used.

[0058] The composite material does not include copolymers of lactic acid and glycolic acid, such as poly(D,L-lactic-co-glycolic acid) or copolymers of poly(lactic) acid and poly(glycolic) acid. Preferably, the biodegradable polymer is a homopolymer (i.e., not a copolymer). Preferably, the composite material of the present invention does not include any copolymers.

[0059] composite material The composite materials of the invention, once formed and prior to use in vivo, are porous: they have an open-cell foam-like structure and are sometimes referred to as "foams."

[0060] The pores in the composite material preferably include nanopores and micropores, where the nanopores are generated by the nano-sized CaP particles and the micropores are generated by the polymer network, the nanopores have a longest dimension of about 1 to about 100 nm, and the micropores have a longest dimension of about 1 to 100 μm.

[0061] Nanopore size can be measured using SEM and / or by nitrogen adsorption and desorption using the Barett-Joyner-Halenda (BJH) method. Micropore size can be measured using SEM and / or by mercury porosimetry.

[0062] The porosity of the composite material can be calculated by measuring the density of an experimental sample and comparing it to the theoretical density of a bulk sample (i.e., a non-porous sample containing equal amounts of polymer and CaP). For example, the density of PCL is 1.14 g / cm 3 and the density of HA is 3.15 g / cm, and the composition has a PCL / HA ratio of 2:1, then the theoretical density of this sample is (2*1.14+3.15) / 3=1.81 g / cm 3 Therefore, a solid cube (non-porous) of this composition with sides of 1 cm should weigh 1.81 g. If a cubic sample of this composition with sides of 1 cm actually weighs 0.181 g, then the porosity would be 1-(0.181 / 1.81)=90%.

[0063] The porous composite materials of the present invention preferably have a porosity in the range of about 20 to about 95%, more preferably in the range of about 50 to about 90%, and even more preferably in the range of about 60 to about 90%. Although a high level of porosity is desirable for promoting bone growth in vivo, highly porous composite materials have low mechanical strength and may not be suitable for all applications.

[0064] The composite may further include additional voids created by the removable support. Such voids may have a longest dimension of about 5 to 40 mm. Voids can be introduced into the composite by solidifying the composite around a removable support, leaving the voids in the composite when the support is removed. For example, the composite may be molded around a removable pin array. After solidification of the composite, the pin array can be removed, leaving voids in the composite corresponding to the shape and size of the pin array. The pins may have any cross-section, but cylindrical pins are preferred. A suitable diameter for the cylindrical pins is about 0.25 to about 2 mm.

[0065] The removable support can be made of metal, such as stainless steel. To aid in the removal of any removable support from the composite material, the surface of the support should be smooth, such as a polished metal surface.

[0066] The presence of millimeter-sized voids in the composite material can, for example, promote vascularization, i.e., the growth of blood vessels, within the composite material in vivo when the composite material is implanted in a patient.

[0067] The composite materials of the present invention are hydrophilic when manufactured and remain hydrophilic as the polymer matrix biodegrades in vivo. By hydrophilic, we mean that the composite has a contact angle with water of <90°. The smaller the contact angle, the more hydrophilic the composite is and the better it will be at promoting bone growth in vivo. The composite preferably has a contact angle with water of about 70° or less, more preferably about 60° or less.

[0068] The contact angle of a sample can be measured by placing a drop of Type 1 water (resistivity of 18.2 MΩ / cm) on a flat portion of the sample and measuring the contact angle between the drop and the sample surface with a goniometer.

[0069] The porosity and hydrophilicity of the composite material, when implanted, promotes rapid infiltration and adsorption of body fluids, bone integration, and the attachment of new bone cells. Over time, the matrix polymer biodegrades, the CaP dissolves, and the composite material is eventually replaced by new bone tissue.

[0070] In the composite of the present invention, the nano-sized CaP is uniformly dispersed throughout the polymer matrix. As a result, some of the CaP is initially completely surrounded by the polymer (i.e., embedded within the polymer) and some is exposed at the polymer surface, including the pore surfaces within the polymer matrix. The exposed CaP makes the composite as a whole hydrophilic, even when a hydrophobic polymer such as PCL or a less hydrophilic polymer such as PLA is used to form the composite.

[0071] Conventional implants, where CaP is present as a surface coating on the polymer structure, are initially hydrophilic, but as the CaP dissolves in vivo, the underlying polymer is exposed. This can be detrimental to new bone growth, as the polymer is much less efficient than CaP at promoting osseointegration. In contrast, in the present invention, CaP is distributed evenly throughout the polymer forming the matrix. The CaP at the surface of the polymer matrix makes the composite initially hydrophilic. As the polymer biodegrades in vivo, the CaP previously surrounded by the polymer is exposed, which helps maintain the hydrophilicity of the composite over time. This results in improved osseointegration and sustains the growth of new bone tissue.

[0072] The composite material of the present invention has an open cell structure, which allows infiltration of new bone cells into the matrix and promotes new bone growth.

[0073] Due to the presence of dispersed CaP, the composite material of the present invention has a higher surface area than a similar porous polymer matrix made without the incorporation of CaP. This indicates that at least a portion of the nano-sized CaP is exposed at the surface of the polymer matrix and contributes to the surface area of ​​the composite material. The preferred surface area of ​​the composite material is 5 to 50 m2. 2 / g, preferably 7 to 50m 2 / g range.

[0074] The stiffness of the composite can be controlled by controlling the relative amounts of polymer and CaP used. Increasing the amount of CaP relative to the amount of polymer increases the stiffness of the composite but tends to make it more brittle. Decreasing the amount of CaP relative to the amount of polymer makes the composite more flexible but less stiff.

[0075] The hydrophilicity of the composite material can also be controlled by controlling the relative amounts of polymer and CaP used, with increasing amounts of CaP used resulting in increased hydrophilicity.

[0076] Suitable weight ratios of CaP to polymer include about 1:4 to about 3:1, preferably 1:3 to about 1:1, and preferably about 1:2. At ratios greater than 1:1, for example 2CaP:1PCL, the composite becomes brittle and more difficult to handle.

[0077] In one embodiment, the composite material of the present invention does not contain any NaCl.

[0078] Once formed, the composite material is preferably ground into particles having a diameter of about 0.1 to about 1 mm, which may be suspended in a pharma- ceutically acceptable solvent. The resulting suspension or paste may then be injected directly into the injury site to promote repair. Suitable pharma- ceutically acceptable solvents for injection include glycerol, water, propylene glycol, and PEG-12. Composite materials containing a CaP to polymer ratio of greater than 1:1 are particularly suitable for grinding into particles.

[0079] method In another aspect, a first method of preparing a porous hydrophilic composite material is provided, the method comprising: (a) mixing a solution of a biodegradable polymer in a first solvent with nanosized calcium phosphate (CaP), preferably a dispersion of nanosized CaP in a second solvent, until the CaP is uniformly distributed throughout the resulting mixture; (b) solidifying the mixture of step (a) to form a gel; and (c) removing the first and second solvents from the gel of step (b) by washing with a third solvent to leave a porous hydrophilic composite material containing nanosized CaP dispersed throughout the porous polymer matrix. Includes.

[0080] The preferred features of the porous composite material discussed above apply equally to the first method and its products.

[0081] Step (a) involves mixing a solution of a biodegradable polymer in a first solvent with nanosized calcium phosphate (CaP), preferably a dispersion of nanosized calcium phosphate (CaP) in a second solvent, until the CaP is uniformly distributed throughout the resulting mixture.

[0082] The first solvent should be one in which the polymer is completely soluble, but the solubility is highly temperature dependent in a suitable temperature range (such as about 0°C to 50°C). A first solvent in which the polymer has limited solubility at temperatures below about 10°C, for example below about 5°C, is preferred. Preferably, the first solvent is one in which the polymer can be completely dissolved in the first solvent within a suitable time at ambient temperate (20°C) or by warming, for example by warming to 50°C or less, such as 40-45°C. Dissolution of the polymer can be promoted by stirring or other agitation of the solvent.

[0083] Preferably, the minimum amount of first solvent necessary to dissolve the polymer is used for cost reasons and to facilitate subsequent solvent removal. The amount of first and second solvent should also not be so high that a gel cannot be formed in step (b). However, the total amount of first and second solvent used will affect the porosity of the final composite material, so the amount of solvent used must be balanced against the desired porosity of the final product; the more solvent, the more porous the composite material will tend to be.

[0084] Nano-sized CaP particles, when added in powder form, tend to agglomerate and are difficult to disperse in polymer solution.Therefore, it is preferred that CaP is used as a dispersion in a second solvent.For example, nano-sized CaP may be synthesized using a method that directly leads to the formation of a suitable dispersion.Preferably, the dispersion of CaP in a second solvent does not contain anything other than CaP and the second solvent.

[0085] The first and second solvents may be the same or different, but are preferably the same. If the first and second solvents are different, the second solvent should be miscible in the first solvent and should not adversely affect the solubility of the polymer.

[0086] When the polymer is a water-insoluble polymer such as PCL, PLA or PGA, suitable first solvents include tetrahydrofuran (THF), dioxane, ethyl acetate and acetone, with acetone being preferred.When the polymer is water-insoluble, suitable second solvents for use include THF, dioxane, ethyl acetate, acetone and mixtures thereof, with acetone being preferred.

[0087] When the polymer is a water-soluble polymer such as poly(vinyl alcohol) (PVA), soluble collagen, hyaluronic acid, gelatin or chitosan, suitable first and second solvents include water, ethanol, methanol and iso-propyl alcohol (IPA), with water being preferred.

[0088] The first and second solvents are preferably biocompatible so that any residual solvent remaining in the porous composite material does not pose a health risk when the composite material is used in vivo For this reason, acetone is the preferred first and second solvent when a water-insoluble polymer is used, and water is the preferred first and second solvent when a water-soluble polymer is used.

[0089] The solution of the biodegradable polymer in the first solvent and the nanosized calcium phosphate (CaP), such as a dispersion of nanosized calcium phosphate (CaP) in the second solvent, should be mixed until the CaP is uniformly distributed throughout the resulting mixture. This may take approximately 1 hour. The uniform distribution of the CaP in the mixture can be assessed visually.

[0090] Once mixing is complete and the CaP is evenly distributed throughout the mixture, the mixture may be allowed to cool until it begins to solidify and form a gel. Conveniently, this can be done by allowing the mixture to cool to room temperature (if necessary) and then placing it in a refrigerator at about 4-5° C. Alternatively, the mixture may be placed directly into the refrigerator. Lower temperatures may also be used, for example 0° C. or below, although these temperatures are less preferred from a processing standpoint.

[0091] Alternatively, the mixture may also be cooled by pouring into a mold that is at a lower temperature than the mixture. For example, the mixture may be poured into a pre-chilled mold. Furthermore, the filled mold may be placed in a refrigerator to complete the solidification to form a gel. The mold may be pre-chilled by placing it in a refrigerator or freezer prior to use.

[0092] In one embodiment, step (b) of the first method preferably comprises cooling the mixture of step (a) to solidify it.

[0093] As the mixture begins to solidify, it forms a gel incorporating CaP and the first and second solvents. The gel that forms may be periodically agitated (e.g., stirred or shaken) to avoid settling of the CaP particles, especially when forming large composite structures that take a long time to solidify. This helps ensure uniform distribution of CaP in the resulting composite.

[0094] Once a gel begins to form, the entire mixture may be transferred to a filter to facilitate the subsequent washing step (c).

[0095] Once solidification of the mixture is substantially complete, the resulting gel is washed with a third solvent to remove the first and second solvents. Removal of the first and second solvents from the solidified gel creates pores within the polymer matrix.

[0096] The set of the mixture can be assessed by observing whether the mixture flows when the container containing the mixture is tilted, or if small waves form on the surface of the mixture when the side of the container is gently tapped, this indicates that the mixture has not yet set.

[0097] The third solvent is different from the first and second solvents. The third solvent should be miscible with the first and second solvents, so that the first and second solvents dissolve in the third solvent and are removed by washing. The third solvent should not be a solvent for the polymer.

[0098] When the polymer is water-insoluble, suitable third solvents include water, IPA, ethanol and methanol.The third solvent is preferably IPA or water, more preferably water.Some shrinkage of gel may occur during the washing process, and water does not cause as much shrinkage as IPA.

[0099] If the polymer is water soluble, suitable third solvents include THF, dioxane, ethyl acetate, ethylene glycol, glycerol and acetone, with acetone being preferred.

[0100] When amorphous HA is used as CaP, the use of water as a third solvent can result in conversion to crystalline HA, so to avoid this, methanol is the preferred third solvent when the CaP is amorphous HA.

[0101] Since the third solvent is not a solvent for the polymer, the washing step (c) may also help promote the eventual solidification of the polymer.

[0102] In a washing step (c), the first and second solvents are removed from the gel leaving behind a porous polymer matrix having nano-sized CaP dispersed throughout.

[0103] In a preferred embodiment, the first and second solvents are both acetone and the third solvent is water. More preferably, the polymer is PCL, the first and second solvents are both acetone and the third solvent is water.

[0104] Traces of water remaining in the porous composite material may render it susceptible to undesirable microbial growth. Thus, if the third solvent is water, after step (c), the resulting porous solid composite material may be washed with a fourth solvent to remove traces of water.

[0105] The fourth solvent should be miscible with water and more volatile than water, so that traces of the fourth solvent can be easily removed by drying the resulting composite material. The fourth solvent should also not be a solvent for the polymer. Suitable fourth solvents include MeOH, EtOH and iso-propyl alcohol (IPA), preferably IPA. IPA is a preferred fourth solvent because it can be easily removed by drying at 40°C, it is not highly toxic even if a small amount remains in the composite material, and it is less hygroscopic than methanol and ethanol, which always contain a small amount of water, and therefore does not leave traces of moisture in the structure.

[0106] The polymer cooling and solidification step (step (b)) may be carried out in a mold to control the shape of the resulting composite. Once the polymer has sufficiently solidified, the composite may be removed from the mold and immersed in a third solvent to remove the first and second solvents. If the third solvent is water, the resulting porous solid shaped composite may be further immersed in a fourth solvent as defined above to remove traces of water.

[0107] Also, voids can be introduced into the composite material by solidifying the composite material around a removable support, which leaves a void in the composite material corresponding to the shape and size of the removable support. For example, the composite material may be molded around a removable pin array. After solidification of the composite material, the pin array can be removed, leaving a void in the composite material corresponding to the shape and size of the pin array. Such voids may take the form of grooves or holes in the composite material, having a longest dimension of about 5 to 40 mm, and a width or diameter of about 0.25 to 2 mm.

[0108] The method of the present invention has several advantages over the prior art methods for forming bone scaffolds.For example, it avoids the use of strong acid, which may dissolve CaP and / or cause polymer degradation.It does not need to be heated to melt the polymer, and the appropriate selection of the first solvent avoids the need to be excessively heated to dissolve the polymer.It is also not usually necessary to cool below 0°C to form gel.

[0109] The mixture formed in step (a) may also be deposited using a 3D printer. This may allow for the layer-by-layer construction of complex shaped composites. The mixture may be ejected from a nozzle immersed in water or another suitable third solvent, depending on the nature of the polymer. The movement of the nozzle may be controlled in the xyz directions, allowing for the controlled layer-by-layer construction of the composite structure.

[0110] Implant formation The composite material of the present invention may be used as a scaffold for the promotion of new bone growth. In some embodiments, the composite material may be combined with a load-bearing non-degradable structure, which may also be referred to as an implant.

[0111] The preferred features of the porous composite materials and methods discussed above are equally applicable to such embodiments.

[0112] In a different method embodiment, the substrate may be dipped into a mixture formed from a biodegradable polymer, a first solvent, nanosized calcium phosphate (CaP) and a second solvent, and subsequently removed. A thin layer of the mixture remains on the surface of the substrate, and when the polymer solidifies and the first and second solvents are removed, a thin layer of the composite material is generated that is present as a coating on the substrate surface. The dipping process may be repeated to build up multiple layers of the composite material on the substrate surface.

[0113] After the immersion step and solidification of the polymer, solvent removal may be performed by immersing the coated substrate in a third solvent. Alternatively, the first and second solvents may be removed by solvent evaporation.

[0114] The use of a third solvent to remove the first and second solvents in step (c) of the first method has been found to result in a high porosity in the resulting composite material, such as from about 50% to about 90%. If the first and second solvents are instead evaporated, the voids in the polymer network left by the evaporation of the solvents tend to collapse and the polymer chains may aggregate to form a denser structure, for example having a maximum porosity of only 10-20%.

[0115] Therefore, the thickness and porosity of the layer on the substrate surface can be controlled by selecting the method used to remove the first and second solvents. If the first and second solvents are removed using a third solvent, as in the first method of the present invention, a porous layer results. Alternatively, if the first and second solvents are removed by evaporation, a thinner layer that is denser (i.e., less porous) results.

[0116] The composite layer formed by dipping may be from about 400 nm to about 100 micrometers thick, for example, from 500 nm to 50 micrometers thick.

[0117] In another aspect, a second method of preparing a hydrophilic composite material for promoting bone growth is provided, said second method comprising: (a1) mixing a solution of a biodegradable polymer in a first solvent with a dispersion of nanosized calcium phosphate (CaP) in a second solvent until the CaP is uniformly distributed throughout the resulting mixture; (b1) solidifying the mixture of step (a) on a substrate to form a gel; and (c1) removing the first and second solvents from the gel of step (b) by solvent evaporation to leave a layer of porous hydrophilic composite material containing nanosized CaP dispersed throughout the surface polymer matrix; Includes.

[0118] The preferred features of the porous composite material and first process discussed above apply equally to the second process and its products.

[0119] Pre-cooling the substrate prior to the dipping step, for example to 4-5° C., can help initiate solidification of the polymer on the substrate surface.

[0120] When the composite material is prepared by immersing the substrate in the mixture, preferably both the first and second solvents are acetone and the polymer is PCL.

[0121] In another embodiment of the first method, at least a portion of the substrate may be fully or partially immersed in the mixture formed in step (a) before the polymer solidifies. The polymer then solidifies around the substrate. After removal of the first and second solvents, a scaffold is formed that contains the substrate partially or completely embedded within the porous composite material.

[0122] In this embodiment, the substrate may be introduced into the mixture in any suitable container, for example, a mold. Alternatively, the substrate may be placed in a mold and then the mixture may be introduced into the mold. If the substrate is placed in a mold, the overall shape of the resulting scaffold is controlled by the shape of the mold. Furthermore, the formation of the composite material may be directed to a surface of the substrate that is not in contact with the mold. For example, FIG. 5b shows the formation of a composite material on the inner surface of a spinal cage. This was produced by placing a case in a suitably shaped Teflon mold with the outer surface of the cage in contact with the mold, and then removing the case from the composite structure.

[0123] Thus, in one embodiment, step (b) of the first method may comprise solidifying the polymer at or around the substrate surface.

[0124] Optionally, one or more layers of composite material may be deposited on the substrate surface by immersion prior to immersing the coated surface in the mixture, allowing for the formation of layers of composite material with different densities and porosities depending on the method used to remove the first and second solvents.

[0125] A denser layer will generally adhere more strongly to the underlying substrate, while a more porous layer will better promote bone ingrowth. In a preferred embodiment, a first layer is formed by evaporating the first and second solvents, and the second and any subsequent layers are formed by washing to remove the first and second solvents.

[0126] Suitable substrates for use in the present invention include orthopedic and dental implants, including, but not limited to, screws, spinal fusion cages, wires, meshes, nails, pins, rods, plates, hip stems, stoma bag ports, bone-anchored hearing aids, and dental implant abutments.

[0127] Suitable substrates include, but are not limited to, metals such as titanium and its alloys, zirconium and its alloys, stainless steel, tantalum, NiTi alloys and cobalt chromium alloys; ceramics such as alumina, zirconia, alumina-reinforced zirconia and Si3N4; graphite materials such as graphene and pyrolytic carbon; and substrates made of polymers such as polypropylene, polyethylene, polysulfone (PSU), polyetherketone (PEKK), poly(styrene), poly(carbonate), poly(ethylene terephthalate) and PEEK. Preferred substrates include titanium and its alloys, zirconium and its alloys, stainless steel, tantalum, NiTi alloys, cobalt chromium alloys, alumina, zirconia, alumina-reinforced zirconia, pyrolytic carbon, polysulfone (PSU), polyetherketone (PEKK), poly(styrene), poly(carbonate) and PEEK. More preferred substrates include titanium and its alloys, stainless steel, zirconia, alumina toughened zirconia, pyrolytic carbon and PEEK, and most preferred substrates include titanium or PEEK.

[0128] The hydrophilicity of the porous hydrophilic composite material formed by the above method may be further increased by treating the composite material with a biocompatible organic polyol. Thus, the method of the present invention comprises, after step (c) or step (c1), (d) immersing the porous hydrophilic composite material in a solution comprising a biocompatible organic polyol; (e) removing the porous hydrophilic composite material from the solution; and (f) drying the porous hydrophilic composite material. It may further include.

[0129] The organic polyol should be biocompatible. Suitable organic polyols include glycerol, propylene glycol, polyvinyl alcohol, or low molecular weight polyethylene glycols such as PEG-12. Suitable polyethylene glycols are those having a molecular weight of about 200 to 2000 g / mol. A preferred polyol is glycerol.

[0130] The polyol is applied to the composite by immersing the composite in a solution of the polyol in a volatile organic solvent. By "volatile organic solvent" is meant a solvent that is more volatile than the polyol. Suitable volatile organic solvents are non-toxic. The solvent should also be completely miscible with the organic polyol. If the polyol is a solid, it should be soluble in the solvent. The solvent should not be a solvent for the polymer in the polymer matrix.

[0131] Suitable volatile organic solvents include isopropanol and ethanol. A suitable solution contains about 0.25-50% by weight of an organic polyol, such as about 0.25-50% by weight of glycerol, in isopropanol. Preferably, the mixture contains at least 0.5% by weight of glycerol in isopropanol.

[0132] Preferably, the composite material is immersed in the solution for up to 10 minutes, more preferably up to 5 minutes. Typically, the composite material will initially float in the solution and then sink as the solution displaces air and fills the pores in the composite material. When the composite material sinks, the pores of the composite material have filled with solution and the composite material no longer emits any visible air bubbles.

[0133] After removing the composite from the solution, the composite is dried to remove the volatile organic solvent. Drying may include placing the composite at room temperature to evaporate the volatile organic solvent. The treated composite may also be heated to hasten the evaporation of the volatile organic solvent. The heating temperature should not be so high as to evaporate the polyol or to damage the polymer matrix. A suitable temperature for such heating is in the range of about 30-40°C, preferably about 35°C. The removal of the volatile solvent may be monitored by weighing the composite during heating. Once the volatile solvent is removed, any increase in weight of the treated composite compared to the starting composite before immersion may be attributed to the polyol.

[0134] Without being bound by theory, it is believed that the polyol is adsorbed onto and / or forms a coating on at least a portion of the interior and / or exterior surfaces of the composite material, thereby increasing its hydrophilicity. By "interior surfaces of the composite material" is meant the surfaces of any pores or voids within the composite material.

[0135] Thus, in another aspect, the present invention provides a porous hydrophilic composite material for promoting bone ingrowth as described herein, further comprising about 0.5-50 wt. % of a biocompatible organic polyol, the weight percent being based on the total weight of the composite material and the biocompatible organic polyol. The biocompatible organic polyol may be adsorbed onto at least a portion of the interior and / or exterior surfaces of the porous hydrophilic composite material and / or may form a coating on at least a portion of the interior and / or exterior surfaces.

[0136] Higher concentrations of biocompatible organic polyols improve hydrophilicity and also make the composite softer and less brittle / fragile.

[0137] All products of the above processes also form part of the present invention.

[0138] Embodiments of the present invention include: Embodiment 1: A porous hydrophilic composite material for promoting bone growth, the composite material comprising: (a) a porous biodegradable polymer matrix, and (b) Approximately 180~380m 2 Nanosized calcium phosphate (CaP) uniformly dispersed throughout the polymer matrix with a specific surface area in the range of 0.1 to 1.0 μm / g Including, Porous hydrophilic composite material. With the proviso that said composite material does not contain any copolymer of lactic acid and glycolic acid.

[0139] Embodiment 2: The porous hydrophilic composite material of embodiment 1, wherein said nano-sized CaP is amorphous calcium phosphate (ACP), beta-TCP, calcium deficient HA (CDHA) or hydroxyapatite (HA).

[0140] Embodiment 3: The porous hydrophilic composite material of embodiment 1, wherein said CaP is nanocrystalline.

[0141] Embodiment 4: The porous hydrophilic composite material of any of the preceding embodiments, wherein said CaP is HA.

[0142] Embodiment 5: The porous hydrophilic composite material of any of embodiments 1-3, wherein said CaP is ACP.

[0143] Embodiment 6: The porous hydrophilic composite material of any of the preceding embodiments, wherein the polymer matrix comprises or consists of poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGL), poly(vinyl alcohol) (PVA), soluble collagen, hyaluronic acid, gelatin, or chitosan.

[0144] Embodiment 7: The porous hydrophilic composite material of any of the previous embodiments, wherein the polymer matrix comprises or consists of ε-poly(caprolactone) (PCL).

[0145] Embodiment 8: The porous hydrophilic composite material of any of the previous embodiments, wherein the ratio of CaP to polymer matrix is ​​from about 1:4 to about 3:1 by weight.

[0146] Embodiment 9: The porous hydrophilic composite material of any of the previous embodiments, comprising nanopores and micropores.

[0147] Embodiment 10: The CaP is about 200 to about 350 m 2 The porous hydrophilic composite material of any of the previous embodiments, having a specific surface area in the range of 0.1 to 1.0 nm / g.

[0148] Embodiment 11: About 5 to about 50 m 2 The porous hydrophilic composite material of any of the previous embodiments, having a specific surface area in the range of 0.1 to 1.0 nm / g.

[0149] Embodiment 12: The porous hydrophilic composite material of any of the preceding embodiments, further comprising about 0.5-50 wt. % of said biocompatible organic polyol, based on the total weight of the composite material comprising said biocompatible organic polyol.

[0150] Embodiment 13: The porous hydrophilic composite material of any of the previous embodiments, wherein the organic polyol is adsorbed onto at least a portion of its interior and / or exterior surfaces and / or forms a coating on at least a portion of its interior and / or exterior surfaces.

[0151] Embodiment 14: The porous hydrophilic composite material of any of the preceding claims, wherein the organic polyol is glycerol, propylene glycol, polyvinyl alcohol, or polyethylene glycol having a molecular weight in the range of about 200 to about 2,000.

[0152]

[0036] Embodiment 15: The porous hydrophilic composite material of any of the preceding embodiments, wherein the organic polyol is glycerol.

[0153] Embodiment 16: The porous hydrophilic composite material of any of the preceding embodiments, having a porosity of 20-95%.

[0154] Embodiment 17: The porous hydrophilic composite material of any of the preceding embodiments, having a porosity of 50-90%.

[0155] Embodiment 18: The porous hydrophilic composite material of any of the preceding embodiments, having a porosity of 60-90%.

[0156] Embodiment 19: The porous hydrophilic composite material of any of the previous embodiments, having a contact angle with water of 70° or less.

[0157] Embodiment 20: The porous hydrophilic composite material of any of the previous embodiments, having a contact angle with water of 60° or less.

[0158] Embodiment 21: A scaffold for use in bone reconstruction comprising a substrate and the porous hydrophilic composite material of any of the preceding embodiments.

[0159] Embodiment 22: The scaffold of embodiment 21, wherein said substrate is selected from an orthopedic implant and a dental implant.

[0160] Embodiment 23: The scaffold of embodiment 22, wherein the substrate is selected from a screw, a spinal fusion cage, a wire, a mesh, a nail, a pin, a rod, a plate, a hip stem, a port of a stoma bag, a bone-anchored hearing aid, and a dental implant abutment.

[0161] Embodiment 24: The scaffold of any of embodiments 21-23, wherein the substrate is made of a metal, a ceramic, a graphitic material or a polymer.

[0162] Embodiment 25: The scaffold of any of embodiments 21-24, wherein the substrate is made of titanium and its alloys, zirconium and its alloys, stainless steel, tantalum, NiTi alloys, cobalt chromium alloys; alumina, zirconia, alumina reinforced zirconia, Si3N4; graphene, pyrolytic carbon; polypropylene, polyethylene, polysulfone (PSU), polyetherketone (PEKK), poly(styrene), poly(carbonate), poly(ethylene terephthalate) or PEEK.

[0163] Embodiment 26: The scaffold of any of embodiments 21 to 25, wherein the substrate is made of titanium and its alloys, zirconium and its alloys, stainless steel, tantalum, NiTi alloys, cobalt chromium alloys, alumina, zirconia, alumina-toughened zirconia, pyrolytic carbon, polysulfone (PSU), polyetherketone (PEKK), poly(styrene), poly(carbonate) or PEEK.

[0164] Embodiment 27: The scaffold of any of embodiments 21-26, wherein the substrate is made of titanium and its alloys, stainless steel, zirconia, alumina-toughened zirconia, pyrolytic carbon or PEEK.

[0165] Embodiment 28: The scaffold of any of embodiments 21 to 27, wherein the substrate is made of titanium or PEEK.

[0166] Embodiment 29: The scaffold of any of embodiments 21 to 28, wherein the composite material is present as a coating on the surface of the substrate.

[0167] Embodiment 30: The scaffold of any of embodiments 21 to 28, wherein the substrate is partially or completely embedded in the composite material.

[0168] Embodiment 31: The scaffold of embodiment 29, wherein said coating comprises at least two layers of different porosity.

[0169] Embodiment 32: The scaffold of embodiment 31, wherein the coating comprises a first layer closest to the substrate having a porosity of less than 20% and a second layer on top of the first layer having a porosity of more than 20%, preferably 50-90%.

[0170] Embodiment 33: A method for preparing a porous hydrophilic composite material for promoting bone growth, the method comprising: (a) mixing a solution of a biodegradable polymer in a first solvent with nanosized calcium phosphate (CaP), preferably a dispersion of nanosized calcium phosphate (CaP) in a second solvent, until the CaP is uniformly distributed throughout the resulting mixture; (b) solidifying the mixture of step (a) to form a gel; and (c) removing the first and second solvents from the gel of step (b) by washing with a third solvent to leave a porous hydrophilic composite material containing nanosized CaP uniformly dispersed in a porous polymer matrix. A preparation method comprising:

[0171] Embodiment 34: The method of embodiment 29, wherein step (a) comprises mixing a solution of the biodegradable polymer in a first solvent with a dispersion of nanosized calcium phosphate (CaP) in a second solvent until the CaP is uniformly distributed throughout the resulting mixture.

[0172] Embodiment 35: The method of embodiment 29 or 30, wherein step (b) is carried out in a mold.

[0173] Embodiment 36: The method of embodiment 29 or 30, wherein steps (b) and (c) comprise printing the mixture of step (a) into a bath of said third solvent.

[0174] Embodiment 37: The method of any of embodiments 29-32, wherein the third solvent is water, isopropyl alcohol (IPA), ethanol, or methanol.

[0175] Embodiment 38: The method of any of embodiments 29-33, wherein the third solvent is IPA or water.

[0176] Embodiment 39: The method of any of embodiments 29-33, wherein the third solvent is water.

[0177] Embodiment 40: The method of any of embodiments 29-32, wherein the third solvent is THF, dioxane, or acetone.

[0178] Embodiment 41: The method of any of embodiments 29-32, wherein the third solvent is acetone.

[0179] Embodiment 42: A method for preparing a hydrophilic composite material, the method comprising: (a1) mixing a solution of a biodegradable polymer in a first solvent with nanosized calcium phosphate (CaP), preferably a dispersion of nanosized calcium phosphate (CaP) in a second solvent, until the CaP is uniformly distributed throughout the resulting mixture; (b1) solidifying the mixture of step (a1) on a substrate to form a gel; and (c1) removing the first and second solvents from the gel of step (b1) by solvent evaporation, leaving a layer of porous hydrophilic composite material containing nanosized CaP dispersed throughout a porous polymer matrix on the substrate. A preparation method comprising:

[0180] Embodiment 43: The method of embodiment 42, wherein step (a1) comprises mixing a solution of a biodegradable polymer in a first solvent with a dispersion of nanosized calcium phosphate (CaP) in a second solvent until the CaP is uniformly distributed throughout the resulting mixture.

[0181] Embodiment 44: The method of embodiment 42 or 43, further comprising, after step (c1), solidifying the further mixture of step (a) on the layer formed in step (c1) to form a gel, and removing said first and second solvents from the gel by washing with a third solvent to leave a porous polymer matrix containing nanosized CaP uniformly dispersed in the polymer matrix on top of the layer, wherein said third solvent is preferably defined in any of embodiments 33 to 37.

[0182] Embodiment 45: The method of any of embodiments 33-44, wherein the first and second solvents are the same.

[0183] Embodiment 46: The method of any of embodiments 33-39 or 42-45, wherein the first and second solvents are independently selected from THF, dioxane, and acetone.

[0184] Embodiment 47: The method of any of embodiments 33-39 or 42-45, wherein the first and second solvents are both acetone.

[0185] Embodiment 48: The method of any of embodiments 33-36 or 40-45, wherein the first and second solvents are independently selected from water, iso-propyl alcohol (IPA), ethanol, or methanol.

[0186] Embodiment 49: The method of any of embodiments 33-36 or 40-45, wherein the first and second solvents are independently selected from IPA or water.

[0187] Embodiment 50: The method of any of embodiments 33-36 or 40-45, wherein the first and second solvents are both water.

[0188] Embodiment 51: The method of any of embodiments 33-50, wherein the CaP is prepared by mixing a dispersion of a non-phosphate calcium salt in a suitable solvent with an aqueous solution of phosphoric acid.

[0189] Embodiment 52: The method of embodiment 51, wherein the non-calcium phosphate salt is calcium oxide or calcium hydroxide.

[0190] Embodiment 53: The method of embodiment 51 or 52, wherein the suitable solvent is water, ethylene glycol, or glycerol.

[0191] Embodiment 54: The method of any of embodiments 33-53, wherein step (b) or step (b1) comprises cooling the mixture of step (a).

[0192] Embodiment 55: The method of any of embodiments 33-54, wherein step (b) or step (b1) comprises solidifying the mixture on or around at least a portion of the substrate.

[0193] Embodiment 56: The method of embodiment 55, wherein the substrate is selected from an orthopedic implant and a dental implant.

[0194] Embodiment 57: The method of embodiment 56, wherein the substrate is selected from screws, spinal fusion cages, wires, meshes, nails, pins, rods, plates, hip stems, stoma bag ports, bone-anchored hearing aids, and dental implant abutments.

[0195] Embodiment 58: The method of any of embodiments 54-57, wherein the substrate is made of a metal, ceramic, graphite material, or polymer.

[0196] Embodiment 59: The method of any of embodiments 54-58, wherein the substrate is made of titanium and its alloys, zirconium and its alloys, stainless steel, tantalum, NiTi alloys, cobalt chromium alloys; alumina, zirconia, alumina reinforced zirconia, Si3N4; graphene, pyrolytic carbon; polypropylene, polyethylene, polysulfone (PSU), polyetherketone (PEKK), poly(styrene), poly(carbonate), poly(ethylene terephthalate), or PEEK.

[0197] Embodiment 60: The method of any of embodiments 54-59, wherein the substrate is made of titanium and its alloys, zirconium and its alloys, stainless steel, tantalum, NiTi alloys, cobalt chromium alloys, alumina, zirconia, alumina-toughened zirconia, pyrolytic carbon, polysulfone (PSU), polyetherketone (PEKK), poly(styrene), poly(carbonate) or PEEK.

[0198] Embodiment 61: The method of any of embodiments 54-60, wherein the substrate is made of titanium and its alloys, stainless steel, zirconia, alumina-toughened zirconia, pyrolytic carbon, or PEEK.

[0199] Embodiment 62: The method of any of embodiments 54-61, wherein the substrate is made of titanium or PEEK.

[0200] (d) immersing the porous hydrophilic composite material in a solution comprising a biocompatible organic polyol; (e) removing the porous hydrophilic composite material from the solution; and (f) drying the porous hydrophilic composite material. 63. The method of any of embodiments 54-62, further comprising:

[0201] Embodiment 64: The method of embodiment 63, wherein the organic polyol is glycerol, propylene glycol, polyvinyl alcohol, or polyethylene glycol having a molecular weight in the range of about 200 to about 2,000.

[0202] Embodiment 65: The method of embodiments 63-64, wherein the organic polyol is glycerol.

[0203] Embodiment 66: The CaP is about 180 to about 380 m 2 The method of any of embodiments 54 to 65, wherein the specific surface area is in the range of 1 / g.

[0204] Embodiment 67: The CaP is about 200 to about 350 m2 The method of embodiment 66, wherein the specific surface area is in the range of 1 / g.

[0205] Embodiment 68: The method of any of embodiments 33-62, wherein the nanosized CaP is amorphous calcium phosphate (ACP), beta-TCP, calcium deficient HA (CDHA) or hydroxyapatite (HA).

[0206] Embodiment 69: The method of any of embodiments 33-63, wherein the CaP is nanocrystalline.

[0207] Embodiment 70: The method of any of embodiments 33-64, wherein the polymer matrix comprises or consists of poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGL), poly(vinyl alcohol) (PVA), collagen, hyaluronic acid, chitin or chitosan.

[0208] Embodiment 71: The method of any of embodiments 33-65, wherein the polymer matrix comprises or consists of poly(caprolactone) (PCL).

[0209] Embodiment 72: The method of any of embodiments 33-66, wherein the ratio of CaP to polymer is from about 1:4 to about 3:1 by weight.

[0210] Embodiment 73: The CaP is about 200 to about 350 m 2 The method of any of embodiments 33 to 72, wherein the specific surface area is in the range of 1 / g.

[0211] Embodiment 74: The method of any of embodiments 63-65, wherein the solution is a solution of a biocompatible organic polyol in a volatile organic solvent.

[0212] Embodiment 75: The method of embodiment 74, wherein the volatile organic solvent is isopropanol or ethanol.

[0213] Embodiment 76: A method for preparing nanosized CaP, the method comprising mixing a dispersion of a non-phosphate calcium salt in a suitable non-aqueous solvent with an aqueous phosphoric acid solution to form amorphous nanosized CaP, and optionally contacting the amorphous CaP with water to convert the amorphous CaP to a different form of CaP.

[0214] Embodiment 77: A product obtainable by the method of any of embodiments 33 to 75.

[0215] Embodiment 78. An injectable formulation comprising a dispersion of particles of the porous hydrophilic composite material of any of embodiments 1-20 or 77 and a pharma- ceutically acceptable solvent.

[0216] Embodiment 79: The injectable formulation of embodiment 78, wherein said pharma- ceutically acceptable solvent is selected from glycerol, water for injection, propylene glycol, and PEG-12.

[0217] Embodiment 80. A method for preparing nano-sized CaP, the method comprising: mixing a dispersion of non-phosphate calcium salt in a suitable non-aqueous solvent with an aqueous solution of phosphoric acid to form amorphous nano-sized CaP; and optionally contacting the amorphous nano-sized CaP with water to convert the amorphous nano-sized CaP to another form of CaP. A preparation method comprising:

[0218] Embodiment 81 The method of embodiment 80, wherein the non-aqueous solvent is selected from glycerol and ethylene glycol.

[0219] The present invention includes any and all combinations of the preferred features and embodiments disclosed herein. In particular, all preferred features of the composite material are also preferred features of the composite material and coated substrate obtainable by the method of the present invention.

[0220] The following examples are non-limiting illustrations of the present invention. EXAMPLES

[0221] chemicals Ethylene glycol (anhydrous, 99%), isopropanol (99.5%), glycerol (anhydrous, 99%), CaO, H3PO4 (85%) and poly(caprolactone) 80000 g / mol (PCL) were obtained from Sigma Aldrich (Sweden).

[0222] analytical equipment A Zeiss FEG-SEM Sigma300 with Gemini optics was used for SEM analysis. For XRD analysis, a Bruker D8 instrument with CuKα radiation (1.54 Å) was used. For nitrogen adsorption analysis, a Micromeritics TriStar instrument was used.

[0223] [Example 1] Synthesis of porous HA / PCL composites 1a) Synthesis of HA gel A schematic of the method is shown in Figures 3a and 3b. In a beaker, 2.82 g of powdered CaO was mixed with 150 ml of H2O and the resulting dispersion was stirred for 1 h. In another beaker, 3.48 g of H3PO4 (85 wt%) was mixed with 150 ml of H2O. The contents of the two beakers were mixed at room temperature and the resulting gel was stirred for 12 h. The gel was then filtered through a grade 4 glass filter and washed extensively with 1 L of water followed by 1 L of acetone. The product was a gel containing nanosized HA (~5 g) and acetone (~25 ml).

[0224] 1b) Analysis of HA gel samples A portion of the gel from step 1a) was dried and analyzed using XRD and nitrogen adsorption. XRD analysis (Figure 1) showed that the sample consisted of crystalline HA. The specific surface area of ​​this sample was found to be 200 m2, as determined by the Brunauer-Emmet-Teller (BET) method. 2 / g.

[0225] 1c) Foam manufacturing The acetone / CaP gel prepared in step 1a) (having a total weight of about 25 g) was transferred to a bottle and 75 ml of acetone was added (bringing the total acetone volume to about 100 ml). The resulting mixture was stirred for 12 hours. In a separate bottle, 10 g of PCL was mixed with 80 ml of acetone and the bottle was heated to 42° C. under stirring for 12 hours to dissolve the PCL. The PCL / acetone mixture was then added to the acetone / CaP gel mixture and stirred at 42° C. for about 1 hour. Stirring was then continued while the mixture was cooled to room temperature. The bottle was then placed in a refrigerator at 4-5° C. for 1 hour with shaking about every 5 minutes. The resulting HA / acetone / PCL gel was placed in a glass filter, which was cooled to 4° C. When the HA / acetone / PCL gel was poured into the glass filter, the mixture immediately solidified to produce a solid HA / acetone / PCL foam. After the foam was allowed to completely solidify at 4° C. for about 60 min, the foam and a glass filter were placed in a Buchner flask at room temperature. The foam was washed with 1 L of water and then with 1 L of isopropanol. The resulting solid foam was dried at 35° C. for 12 h to obtain a PCL / HA composite.

[0226] 1d) Foam analysis A sample of the foam produced in step 1c) was sputtered with gold and analyzed using SEM. A representative image is shown in Figure 10. As can be seen from this image, the pore size of the foam is between 0.25 and 10 μm. No large aggregates of HA are visible, and it can also be seen that the HA crystals are uniformly distributed in the polymer matrix.

[0227] A portion of the foam was also analyzed by nitrogen adsorption (BET). Analysis of the foam revealed a specific surface area of ​​22.0 m 2 / g. As a comparison, a pure PCL foam was also synthesized. This was done using the procedure described in step 1c) without any CaP / acetone addition and a total of 160 ml acetone (plus 80 ml of acetone to compensate for the extra amount coming from the acetone / CaP gel). The pure PCL foam had a mass of 6.2 m2 / g.

[0228] Pure porous PCL foam prepared according to Example 1d and composite prepared according to Example 1c were immersed in toluidine blue. The more hydrophilic the composite, the greater the extent to which toluidine blue penetrates into the interior of the structure. Figure 4 shows the results of this test, with Figure 4a showing the exterior of the foam, Figure 4b showing the interior of the foam of Example 1d after immersion, and Figures 4c and 4d showing the exterior and interior of the composite of Example 1c after immersion, respectively. As can be seen by comparing Figures 4a and 4b with Figures 4c and 4d, the composite of the present invention was more hydrophilic than the pure PLC foam.

[0229] [Example 2] Synthesis of porous ACP / PCL composites using ethylene glycol 2a) Synthesis of ACP gel In a beaker, 135 g ethylene glycol and 2.82 g CaO were mixed with 15 ml H2O. In another beaker, 135 g ethylene glycol and 3.48 g H3PO4 were mixed with 15 ml H2O. The contents of each beaker were stirred separately for 30 minutes. The contents of the two beakers were then mixed at room temperature and the resulting gel was stirred for 24 hours. The gel was filtered in a grade 4 glass filter and washed thoroughly with 2 L of isopropanol followed by 1 L of acetone. The product was a gel containing nano-sized ACP (approximately 5 g) and acetone (approximately 25 ml).

[0230] 2b) Analysis of gel samples A sample of the gel produced in step 2a) was dried and analyzed by XRD and nitrogen adsorption (BET). The XRD results showed that an amorphous calcium phosphate was obtained (Figure 2). The specific surface area, determined by the BET method, was 315 m 2 / g.

[0231] 2c) Foam manufacturing The acetone / CaP gel prepared in step 2a) was transferred to a bottle and 75 ml of acetone was added. The resulting mixture was stirred for 12 hours. In a separate bottle, 10 g of PCL was mixed with 80 ml of acetone and the bottle was heated to 42° C. under stirring for 12 hours to dissolve the PCL. The PCL / acetone mixture was then transferred to the acetone / CaP gel mixture and stirred at 42° C. for about 1 hour. The mixture was then cooled to room temperature while stirring was continued. It was then placed in a refrigerator at 4-5° C. for 1 hour with shaking about every 5 minutes. The resulting ACP / acetone / PCL gel was placed in a glass filter and cooled to 4° C. The ACP / acetone / PCL gel was poured into the glass filter and the mixture immediately solidified to produce a solid ACP / acetone / PCL foam. The foam was allowed to completely solidify at 4° C. for about 60 minutes, after which the foam and glass filter were placed in a Buchner flask at room temperature. The foam was washed with 1 L of methanol, then with 1 L of isopropanol. The resulting solid foam was dried at 35° C. for 12 hours.

[0232] [Example 3] Synthesis of porous HA / PCL composites using ethylene glycol 3a) Synthesis of HA In a beaker, 135 g ethylene glycol and 2.82 g CaO were mixed with 15 ml H2O. In another beaker, 135 g ethylene glycol and 3.48 g H3PO4 were mixed with 15 ml H2O. The contents of the beakers were stirred separately for 30 minutes. The contents of the two beakers were then mixed at room temperature. 1000 ml water was poured into the mixture. The mixture was stirred for 3 days and the resulting gel material was filtered in a grade 4 glass filter and washed thoroughly with 2 L of acetone. The product was a gel containing nano-sized HA (approximately 5 g) and acetone (approximately 25 ml).

[0233] 3b) Analysis of gel samples A sample of the gel produced in step 3a was dried and analyzed using XRD and nitrogen adsorption (BET). The XRD results showed that nano-sized hydroxyapatite was obtained. The specific surface area was calculated to be 320 m by the BET method. 2 / g.

[0234] 3c) Foam manufacturing The mixture prepared in step 3a) was treated according to step c) of Example 2 to prepare a foam.

[0235] [Example 4] Synthesis of porous ACP / PCL composites using glycerol The composite material was prepared as described in Example 2, substituting glycerol for ethylene glycol. The specific surface area of ​​the ACP powder was measured to be 318 m 2 / g.

[0236] [Example 5] Fabrication of HA / PCL coatings on glass surfaces A CaP / acetone / PCL mixture was prepared according to Examples 1a-1c, but instead of cooling the CaP / acetone / PCL mixture to 4° C., the mixture was kept at 42° C. A glass slide (O. Kindler GmbH, 26x76 mm) used for microscopy was immersed in the mixture and removed. The acetone was then allowed to evaporate from the slide, resulting in a thin, uniform CaP / PCL film on the surface of the slide.

[0237] The adhesive strength of the CaP / PCL film to the glass surface was evaluated by the Scotch® tape test using Scotch® tape (810, 3M). This test involves placing the Scotch® tape on a microscope slide coated with CaP / PCL, then applying a load (1 kg) for about 30 seconds, after which the tape is removed and the amount of CaP / PCL film present on the tape and on the glass slide is qualitatively evaluated by visual inspection. As a result, the CaP / PCL film was not significantly affected by the Scotch® tape test, i.e., the CaP / PCL film was well adhered to the substrate.

[0238] [Example 6] In situ formation of HA / PCL composite in PEEK spinal cage implants A CaP / acetone / PCL mixture was prepared according to Examples 1a-1c, but instead of cooling the CaP / acetone / PCL mixture to 4° C., the mixture was maintained at 42° C. A PEEK cage (shown in FIG. 5a) was placed into a Teflon mold with an insert molded in the same shape of the interior channel as the PEEK cage, with a 2 mm gap between the mold and the PEEK cage channel. The Teflon mold and PEEK cage were cooled to 4° C. The CaP / acetone / PCL mixture was poured into the gap between the cage and the mold, and the mixture was allowed to solidify for 60 minutes. The cage and mold were placed in water for 60 minutes, and the mold was carefully removed, leaving a thin layer of composite on the inner channel surface of the PEEK cage (shown in FIG. 5b). The PEEK cage was flushed with isopropanol and allowed to dry at room temperature.

[0239] [Example 7] In situ formation of CaP / PCL composites on titanium lattices A porous titanium substrate with a truss length of 2.5 mm, pre-cooled to 4° C., was fully immersed in a mixture of CaP / acetone / PCL (prepared as in Examples 1a-1c, but instead of cooling the CaP / acetone / PCL mixture to 4° C., the mixture was kept at 42° C.) and then placed at 4° C. to induce solidification. After about 60 minutes, the excess CaP / acetone / PCL foam around the structure was removed. The acetone was replaced by immersing the substrate in a beaker containing 100 ml of water for 10 minutes, then immersed in a beaker containing 100 ml of isopropanol for 10 minutes, followed by drying at room temperature. The resulting product was a porous structure with CaP / PCL foam infiltrating the titanium structure and filling the pores in the titanium substrate (see FIGS. 6a and 6b).

[0240] This procedure was tested on various titanium porous structures and the samples were then immersed in a 1 wt% solution of alizarin red, which selectively stained the calcium. The samples were then washed in water to remove the excess alizarin red. As shown in Figure 6c, the structures were completely stained red, indicating that the calcium phosphate was evenly distributed in the polymer matrix.

[0241] [Example 8] In situ formation of CaP / PCL composite for producing coatings on implant screw surfaces A CaP / acetone / PCL mixture was prepared according to Examples 1a-1c, but instead of cooling the CaP / acetone / PCL mixture to 4° C., the mixture was maintained at 42° C. A pedicle screw for spinal fusion was immersed in the mixture and then placed in water for 10 minutes, which produced a thin coating of CaP / PCL foam. The screw was then placed in isopropanol for 10 minutes and allowed to dry at room temperature. An image of the screw is shown in FIG. 7.

[0242] [Example 9] Implants of porous HA / PCL composites in rabbit calvaria HA / PCL foams were prepared as described in Example 1. Using appropriate tools, cylindrical plugs with a diameter of 5 mm and a height of 6 mm were punched out of the foam. The plugs were sterilized using E-beam radiation (5KGy). Holes with a diameter of 6 mm were drilled in the rabbit's calvaria. Sterilized foam plugs were then implanted in some of the holes, while some were left unimplanted as controls (sham) to evaluate the ability of the HA / PCL foam composite to induce bone formation. Holes with and without implants were allowed to heal for 6 weeks. The animals were then euthanized and the areas were imaged by micro-CT. The samples were subsequently processed for histological morphometry.

[0243] Figure 8 shows a micro-CT image of a control sham (image a) and a hole with a foam plug inserted (image b). As can be seen in image b, the composite material was fully grown with new bone, while the sham showed little or no new bone growth. This shows that the porous composite material of the present invention can promote bone growth in defects that are too large for natural repair.

[0244] Figure 9 shows a histology slide of the sample in Figure 8b. The slide confirms that the composite was grown with a thin layer of new bone. New bone formation was also observed on the bottom surface of the composite. Irregularities along the edges of the composite indicate that the composite was partially biodegraded during the implant period.

[0245] [Example 10] Formation of regularly distributed pores in composite materials A foam was produced according to Example 1c. A pin array with regularly-spaced pins made of 316 stainless steel, 0.9 mm in diameter, 30 mm in length, and 5 mm spacing between the pins, was placed in the foam (15 g) after a water washing procedure, as shown in Figure 11. The foam was then washed with isopropanol, the pin array was removed, and the foam was dried at 35°C for 12 hours. The result was a foam composite with regularly-spaced cylindrical channels, each with a diameter of 0.9 mm.

[0246] [Example 11] Improving the hydrophilicity of composite materials using 1,2,3-propanetriol (glycerol) A group of foams was produced according to Example 1c. A mixture of 0.5 wt% glycerol in isopropanol was prepared. Approximately 1 g of foam was immersed in 50 mL glycerol / isopropanol mixture for 30 minutes. The foam piece was then removed from the solution and dried at 35°C for 12 hours. The foam piece was then immersed in 1 wt% Azorubin dye type 1 aqueous solution for 30 minutes, after which a cross-section of the foam was photographed (Figure 12b). A second foam piece synthesized according to Example 1c without any glycerol / isopropanol treatment was also immersed in red dye for 30 minutes, after which a cross-section of the foam was photographed (Figure 12a). The dye did not reach the inner part of the untreated foam piece (white area in Figure 12a). In the case of the glycerol / isopropanol treated foam pieces, the dye completely wetted the entire foam piece (Figure 12b), indicating that the glycerol treatment increased the hydrophilicity and, therefore, the wettability of the foam by the dye.

[0247] [Example 12] Fabrication of HA / PCL composites with different CaP / PCL ratios In addition to the CaP / PCL weight ratio of 33.3:66.7 described in Example 1c, a series of foams were made according to Example 1c with varying CaP / PCF weight ratios. A qualitative description of the properties of the various composites is as follows:

[0248] 0CaP / 100PCL: formed a flexible and soft foam that was easily deformed and hydrophobic. The porosity was about 90%.

[0249] 10CaP / 90PCL: had similar properties to 0CaP / 100PCL. Hydrophobic.

[0250] 20CaP / 80PCL: Soft and flexible. Easily deformed. Hydrophilic. Porosity was 85-90%.

[0251] 33.3CaP / 66.7PCL: Soft and flexible, harder than 20CaP / 80PCL. Hydrophilic.

[0252] 50CaP / 50PCL: Hard and somewhat brittle. Very hydrophilic. The composite was broken into granules with a scalpel and mixed with water to form a moldable, voluminous putty. Porosity was approximately 80%.

[0253] 75CaP / 25PCL: Very hard and brittle. Formed a dense structure with 60-70% porosity. Very hydrophilic. The composite was crushed into granules in a mortar and the granules were then mixed with 50% by weight of glycerol to form an injectable paste.

Claims

1. 1. A porous hydrophilic composite material for promoting bone growth, said composite material comprising: (a) a porous biodegradable polymer matrix; (b) Approximately 180 to approximately 380m 2 nanosized calcium phosphate (CaP) uniformly dispersed throughout the polymer matrix, the specific surface area being in the range of 1 / g; (c) about 0.5 to 50 wt. % of the biocompatible organic polyol, based on the total weight of the composite material including the biocompatible organic polyol. Contains Porous hydrophilic composite material. provided that the composite material does not contain any copolymer of lactic acid and glycolic acid.

2. 2. The porous hydrophilic composite material of claim 1, wherein the nano-sized CaP is amorphous calcium phosphate (ACP), beta-TCP, calcium-deficient HA (CDHA) or hydroxyapatite (HA).

3. 10. The porous hydrophilic composite material of claim 1, wherein the CaP is nanocrystalline.

4. 3. The porous hydrophilic composite material of claim 1 or claim 2, wherein the CaP is amorphous.

5. The CaP is about 200 to about 350 m 2 3. The porous hydrophilic composite material according to claim 1, having a specific surface area in the range of 0.1 to 1.0 μm / g.

6. 3. The porous hydrophilic composite material of claim 1 or claim 2, wherein the polymer matrix comprises or consists of poly(caprolactone) (PCL), poly(lactic acid) (PLA), poly(glycolic acid) (PGL), poly(vinyl alcohol) (PVA), soluble collagen, hyaluronic acid, glycerin, or chitosan.

7. 3. The porous hydrophilic composite material of claim 1 or claim 2, wherein the polymer matrix comprises or consists of poly(caprolactone) (PCL).

8. 3. The porous hydrophilic composite material of claim 1 or claim 2, wherein the ratio of CaP to polymer matrix is from about 1:4 to about 3:1 by weight.

9. Approximately 5 to 50 m 2 3. The porous hydrophilic composite material according to claim 1, having a specific surface area in the range of 0.1 to 1.0 μm / g.

10. 3. The porous hydrophilic composite material of claim 1 or claim 2, wherein the organic polyol is adsorbed onto at least a portion of its internal and / or external surface and / or forms a coating on at least a portion of its internal and / or external surface.

11. 3. The porous hydrophilic composite material of claim 1 or claim 2, wherein the organic polyol is polyethylene glycol, glycerol, propylene glycol, or polyvinyl alcohol having a molecular weight ranging from about 200 g / mol to about 2,000 g / mol.

12. 12. The porous hydrophilic composite material of claim 11, wherein the organic polyol is glycerol.

13. 10. A scaffold for use in bone reconstruction, comprising a substrate and the porous hydrophilic composite material of claim 1 or claim 2.

14. The scaffolding of claim 13 , wherein the substrate is selected from an orthopedic implant and a dental implant.

15. 15. The scaffolding of claim 14, wherein the substrate is selected from a screw, a spinal fusion cage, a wire, a mesh, a nail, a pin, a rod, a plate, a hip stem, a port portion of a stoma bag, a bone-anchored hearing aid, and a dental implant abutment.

16. The scaffolding of claim 13 , wherein the substrate is made from a metal, ceramic, graphite material or polymer.

17. 14. The scaffolding of claim 13, wherein the substrate is made from titanium and its alloys, stainless steel, zirconia, alumina-toughened zirconia, pyrolytic carbon, or PEEK.

18. A method for preparing the porous hydrophilic composite material of claim 1 or claim 2, said method comprising: (a) mixing a solution of a biodegradable polymer in a first solvent with a dispersion of nanosized calcium phosphate (CaP) in a second solvent until the CaP is uniformly distributed throughout the resulting mixture; (b) solidifying the mixture of step (a) to form a gel; (c) removing the first and second solvents from the gel of step (b) by: (i) washing with a third solvent to leave a porous hydrophilic composite material containing said nanosized CaP uniformly dispersed in a porous polymer matrix; or (ii) solvent evaporation leaving a porous hydrophilic composite layer containing said nanosized CaP dispersed throughout a polymer matrix on the surface; (d) immersing the porous hydrophilic composite material in a solution containing a biocompatible organic polyol; (e) removing the porous hydrophilic composite material from the solution; and (f) drying the porous hydrophilic composite material A preparation method comprising:

19. 20. The method of claim 18, wherein the third solvent is IPA or water.

20. 20. The method of claim 18, wherein the first and second solvents are the same.

21. 20. The method of claim 18, wherein the first and second solvents are independently selected from THF, dioxane, and acetone.

22. The method of claim 21, wherein the first and second solvents are both acetone.

23. The CaP is about 180 to about 380 m 2 19. The method of claim 18, wherein the sintered body has a specific surface area in the range of 1 / g.

24. The CaP is about 200 to about 350 m 2 24. The method of claim 23, wherein the specific surface area is in the range of 1 / g.

25. 10. An injectable formulation comprising a dispersion of particles of the porous hydrophilic composite material of claim 1 or claim 2 and a pharmaceutically acceptable solvent.

26. 26. The injectable formulation of claim 25, wherein the pharmaceutically acceptable solvent is selected from glycerol, water for injection, propylene glycol, and PEG-12.

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