US20110140295A1 - Electrospun Apatite/Polymer Nano-Composite Scaffolds - Google Patents

Electrospun Apatite/Polymer Nano-Composite Scaffolds Download PDF

Info

Publication number
US20110140295A1
US20110140295A1 US12/971,235 US97123510A US2011140295A1 US 20110140295 A1 US20110140295 A1 US 20110140295A1 US 97123510 A US97123510 A US 97123510A US 2011140295 A1 US2011140295 A1 US 2011140295A1
Authority
US
United States
Prior art keywords
plla
particles
scaffold
scaffolds
fibers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/971,235
Inventor
Mei Wei
Fei Peng
Zhi-kang Xu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Connecticut
Original Assignee
University of Connecticut
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Connecticut filed Critical University of Connecticut
Priority to US12/971,235 priority Critical patent/US20110140295A1/en
Assigned to UNIVERSITY OF CONNECTICUT reassignment UNIVERSITY OF CONNECTICUT ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: XU, ZHI-KANG, PENG, FEI, WEI, MEI
Publication of US20110140295A1 publication Critical patent/US20110140295A1/en
Assigned to NATIONAL SCIENCE FOUNDATION reassignment NATIONAL SCIENCE FOUNDATION CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF CONNECTICUT HEALTH CENTER
Assigned to NATIONAL SCIENCE FOUNDATION reassignment NATIONAL SCIENCE FOUNDATION CONFIRMATORY LICENSE (SEE DOCUMENT FOR DETAILS). Assignors: UNIVERSITY OF CONNECTICUT
Abandoned legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02Prostheses implantable into the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/24Structurally defined web or sheet [e.g., overall dimension, etc.]
    • Y10T428/24058Structurally defined web or sheet [e.g., overall dimension, etc.] including grain, strips, or filamentary elements in respective layers or components in angular relation
    • Y10T428/24124Fibers
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2913Rod, strand, filament or fiber
    • Y10T428/2922Nonlinear [e.g., crimped, coiled, etc.]
    • Y10T428/2924Composite
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00Stock material or miscellaneous articles
    • Y10T428/29Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2913Rod, strand, filament or fiber
    • Y10T428/2927Rod, strand, filament or fiber including structurally defined particulate matter

Definitions

  • the present invention relates generally to composite materials.
  • the present invention also relates generally to methods of making composite materials.
  • Some surgeons remove bone or tissues from one portion of a patient's body and reattach the bone or tissues in another portion of the patient's body. For example, during spinal surgery, bone from the hip is sometimes removed and incorporated into the spine. Some other surgeons are forced to incorporate metal components (e.g., metal rods and/or plates) in portions of a patient's body where natural bone has been shattered or has deteriorated.
  • metal components e.g., metal rods and/or plates
  • natural bone is a composite material that includes hydroxyapatite (HA) and fibrous collagen.
  • HA hydroxyapatite
  • fibrous collagen In natural bone, the HA crystals are embedded within the collagen fiber matrix and are aligned along the long axis of fibers.
  • an apatite/fibrous polymer nano-composite scaffold has been fabricated using electrospinning Electrospinning is a convenient and versatile fabrication technique which produces fibers with diameters from approximately 50 nm to several micrometers.
  • the structure generated by electrospinning is highly porous with interconnected pores. This fibrous structure typically resembles the architecture of an extracellular matrix (ECM). These fibrous structures may be used as artificial bone composite. Furthermore, these fibrous structures may be used with other tissues based on biocompatibility, mechanical properties, and cell attachment and growth of the fibrous structures and the tissues.
  • HA particles with sizes ranging from approximately 10 nm to approximately 10 ⁇ m and having an average aspect ratio up to approximately 50 are synthesized.
  • the HA particles are well dispersed in the spinning dope and co-electrospun with polymer nanofibers.
  • the HA/PLLA nano-composite fibrous scaffold can be fabricated with HA particles homogenously distributed within the PLLA nanofibers.
  • HA nanoparticles up to approximately 20 wt % is incorporated into the PLLA nanofibers. These nanoparticles are well aligned along the long axes of the polymer fibers. Such obtained microstructure closely mimics the micro-arrangement of the inorganic/organic components in the ECM of natural bone.
  • Such fabricated scaffolds have desirable mechanical properties and good cell signaling properties. At least in view of the above, such scaffolds are suitable for loading cells and biological active agents. It should also be noted that incorporation of more than 20 wt % HA nanoparticles is also within the scope of certain embodiments of the present invention.
  • a structure that includes a scaffold and highly crystallized, well-dispersed HA nanoparticles.
  • the HA nanoparticles have controllable aspect ratios within the range of approximately 5 and approximately 50.
  • a structure that includes a fibrous matrix that itself includes a plurality of fibers.
  • the structure also includes a plurality of hydroxyapatite (HA) particles dispersed within the fibrous matrix, wherein the HA particles are substantially aligned along long axes of the plurality of fibers.
  • HA hydroxyapatite
  • a method of forming a structure includes adding hydroxyapatite (HA) particles to a poly-(L-lactic acid) (PLLA) solution to form a mixture and forming an HA/PLLA fiber by electrospinning the mixture.
  • HA hydroxyapatite
  • PLLA poly-(L-lactic acid)
  • a structure that includes a fibrous matrix including a plurality of fibers.
  • the structure also includes a plurality of hydroxyapatite (HA) particles dispersed within the fibrous matrix, wherein the HA particles are substantially aligned along long axes of the plurality of fibers, wherein the structure is manufactured by adding the HA particles to a poly-(L-lactic acid) (PLLA) solution to form a mixture and by forming HA/PLLA fibers by electrospinning the mixture to form the fibrous matrix.
  • HA hydroxyapatite
  • FIGS. 1( a )-( c ) illustrate morphologies of electrospun PLLA and HA/PLLA composite nanofibers. More specifically, FIG. 1( a ) illustrates a field emission scanning electron microscope (FESEM) image of electrospun PLLA nanofibers, FIG. 1( b ) illustrates an FESEM image of HA/PLLA (20:80 w/w) composite nanofibers, and FIG. 1( c ) illustrates a transmission electron microscope (TEM) image of HA/PLLA/HA (20:80 w/w) composite nanofibers.
  • FESEM field emission scanning electron microscope
  • TEM transmission electron microscope
  • FIGS. 2( a )-( f ) illustrate the effect of varying various electrospinning parameters.
  • FIG. 2( a ) illustrates the effect of varying PLLA concentration in the electrospinning dope.
  • FIG. 2( b ) illustrates the effect of varying the amount of HA incorporation (wt %) in the composite fibers.
  • FIG. 2( c ) illustrates the effect of varying power voltage.
  • FIG. 2( d ) illustrates the effect of varying the injection rate.
  • FIG. 2( e ) illustrates the effect of varying the spinneret inner diameter.
  • FIG. 2( f ) illustrates the effect of varying the distance between the spinneret tip and the collector on the diameter of the electrospun nanofibers.
  • FIGS. 3( a )-( c ) illustrate functionalized PLLA fibers.
  • FIG. 3( a ) is a TEM image of polyethylene glycol (PEG)-core-PLLA-shell nanofibers.
  • FIG. 3( b ) is an FESEM image of highly aligned PLLA nano fibers.
  • FIG. 3( c ) is an FESEM image of highly porous PLLA nano fibers.
  • FIGS. 4( a )-( c ) illustrate the mechanical properties of electrospun PLLA and HA/PLLA scaffolds.
  • FIG. 4( a ) illustrates typical stress v. strain curves for HA/PLLA electrospun scafolds with an averaged fiber diameters equal to 110 ⁇ 15 nm.
  • FIG. 4( b ) illustrates Young's moduli (E, hatched bars) and tensile stresses (solid bars) of HA/PLLA electrospun scaffolds with averaged fiber diameters equal to 110 ⁇ 15 nm.
  • FIG. 4( c ) illustrates Young's moduli (E) and tensile stresses of different component HA/PLLA electrospun scaffolds with averaged fiber diameters equal to 170 ⁇ 25 nm.
  • FIGS. 5( a ) and ( b ) illustrate the mechanical properties of electrospun fibrous scaffolds with different compositions and fibrous assemblies.
  • FIG. 5( a ) illustrates the stress vs. strain curves for electrospun fibrous scaffolds with different compositions and fibrous assemblies.
  • FIG. 5( b ) illustrates the tensile test results for electrospun fibrous scaffolds with different compositions and fibrous assemblies.
  • FIGS. 6( a )-( e ) illustrate PLLA nanofibers obtained from electrospinning according to certain embodiments of the present invention.
  • FIG. 6( a ) illustrates the average diameters and standard variations for fibers electrospun from different PLLA concentrations.
  • FIG. 6( b )-( e ) were all taken at a magnification of ⁇ 20,000.
  • FIGS. 7( a )-( d ) illustrate electrospun HA/PLLA composites.
  • the HA particles in the composite were synthesized via a metathesis reaction at 100° C. in FIG. 6( a ), via a metathesis reaction at 70° C. in FIG. 7( b ), via a metathesis reaction at 95° C. in FIG. 7( c ), and via a urea decomposition at 95° C. in FIG. 7( d ).
  • HA particles with different sizes and aspect ratios are evenly distributed within the illustrated polymer nanofibers.
  • the composites illustrated in FIGS. 7( a )-( d ) demonstrate a good orientation along the long axis of the PLA nanofibers.
  • the HA content in these composites are 20 wt %.
  • FIGS. 8( a )-( b ) illustrate thin layers of a biomimetic apatite coating on the surface of PLLA and HA/PLLA scaffolds, respectively.
  • FIG. 9 illustrates in vitro release of FITC-BSA from electrospun HA/PLLA fibrous scaffold with needle-shape HA particles either at nano-(NHA) or microsize (MHA) and with either random or aligned fibrous assembly.
  • FIG. 10 illustrates relative cell viability on different scaffolds after being cultured for 3, 7, and 10 days.
  • Sample A PLLA scaffold with random assembly
  • Sample B micrometer-size HA/PLLA scaffold with random assembly
  • Sample C nanometer-size HA/PLLA scaffold with random assembly
  • Sample D biomimetic apatite-coated nanometer-size HA/PLLA scaffold with random assembly
  • Sample E micrometer-size HA/PLLA scaffold with aligned assembly
  • sample F nanometer-size HA/PLLA scaffold with aligned assembly.
  • FIG. 11 illustrates relative alkaline phosphatase (ALP) activities on different scaffolds after being cultured for 7 and 10 days.
  • ALP alkaline phosphatase
  • HA/PLLA composite scaffolds are electrospun.
  • other composite systems using materials other than HA and PLLA are also within the scope of certain embodiments of the present invention.
  • collagen, hyaluronans, fibrin, chitosan, alginate, other animal- or plant-derived polymers, PLA, PCL, PGA, other synthetic and natural polymers, polyesters, polyethers, polycarbonates, polyamines, polyamides, and their co-polymers and combinations may be used.
  • carbonated HA, and other calcium phosphates e.g., ion-substituted apatites, such as carbonate hydroxyapatite, fluorinated hydroxyapatite, chlorinated hydroxyapatite, silicon-containing hydroxyapatite, magnesium-containing hydroxyapatite and other ion substituted HA, tricalcium phosphate, tetracalcium phosphate, monetite, dicalcium phosphate, dicalcium phosphate dihydrate, octacalcium phosphate, or calcium sulfate) may also be used.
  • ion-substituted apatites such as carbonate hydroxyapatite, fluorinated hydroxyapatite, chlorinated hydroxyapatite, silicon-containing hydroxyapatite, magnesium-containing hydroxyapatite and other ion substituted HA, tricalcium phosphate, tetracalcium phosphate, monetite
  • HA particles were added to a PLLA solution to fabricate an HA/PLLA composite. Also, the amount of HA in the PLLA solution was adjusted by varying the HA to PLLA feeding ratio in the spin-dope.
  • up to approximately 20 wt % of HA is incorporated into PLLA nanofibers.
  • These HA particles are typically well aligned along the long axis of the polymer fibers.
  • the size of the HA particles have an average width of at least 10 nm and an average length ranged from approximately 10 nm to approximately 10 ⁇ m, with an average aspect ratio up to approximately 50.
  • the particles, according to certain embodiments of the present invention were homogenously distributed within the PLLA nanofibers after electrospinning The resultant microstructure closely mimicked the arrangement of the inorganic/organic components in ECM of natural bone.
  • the HA/PLLA scaffold has improved mechanical properties and biocompatibility.
  • HA particles with lengths between 100 and 200 nm and aspect ratios between 7 and 10 were evenly distributed within HA/PLLA fiber bodies. These particles also demonstrated a good orientation along the long axes of the PLLA nanofibers.
  • FIG. 2 The effects of altering the electrospinning processing parameters on the diameter of HA/PLLA composite fibers were studied in FIG. 2 .
  • varying the polymer concentration of the electrospinning dope and varying the HA/PLLA weight ratio have the most obvious influences on the diameter.
  • FIG. 2( a ) the diameter of composite nanofibers increase with the PLLA concentration in the spinning dope, which indicates that a high PLLA concentration dope has higher surface tension and was more difficult to be spun into finer fibers during the fiber spinning process.
  • FIG. 2( b ) illustrates that composite fiber diameter decreases with increasing HA weight ratio. This is likely explained by the fact that higher amounts of HA in a composite decreases the viscosity of the electrospinning dope and the surface tension thereof as well.
  • FIG. 3 several modified electrospinning techniques for fabricating functionalized nanofibrous scaffolds have been implemented according to various embodiments of the present invention.
  • a PEG/PLLA core-shell structure has been co-electrospun into a fibrous composite scaffold using co-axial dual spinnerets, as shown in FIG. 3( a ).
  • highly aligned nanofibers were fabricated using a rotating drum as the collector, as illustrated in FIG. 3( b ). Scaffolds prepared in this manner have good orientation and improved mechanical strength along the long axes of the fibers.
  • the porosity and pore size of fibers according to certain embodiments of the present invention can be adjusted by altering the solvent used and dope concentration.
  • the porous surface of the fibers can be used, for example, for controlled delivery of growth factors.
  • the porous surface will also enhance the bonding strength between the polymer fiber and a biomimetic apatite coating, such as the one illustrated in FIG. 8( b ).
  • the porous surface may also act as a nucleation site for apatite further growth.
  • FIG. 4 compares mechanical properties of various electrospun composite fibers with different HA incorporation ratios.
  • One of skill in the art will recognize, upon analyzing FIGS. 4( a )-( c ), that both the Young's moduli and tensile stresses of the electrospun mats increased continuously as the HA incorporation ratio increased. This can be explained by the fact that HA, when well dispersed and aligned along fiber long axes, plays a substantial role in reinforcing the composite fibrous mat. Comparisons between the data included in FIG. 4( b ) and FIG. 4( c ) also demonstrates that fibrous mats with thicker composite nanofibers present more desirable mechanical properties.
  • FIG. 5( a )-( b ) illustrates the mechanical properties of electrospun PLLA-based scaffolds using tensile test.
  • One of skill in the art will recognize that both the alignment of the scaffold assembly and the incorporation of nano-size, needle-shape HA particles into the nano-fibers significantly improved the elastic modulus of the composite scaffold.
  • the scaffold with HA particles are much stiffer than those without HA particles, and the elastic modulus of the former is more than two times as high as that of the later. It is also shown that, the HA nanoparticles inhibit un-folding and orientation of PLLA molecular chains within spun fibers during tensile testing, i.e. cold drawing of the scaffold, and decrease the toughness of the composite scaffolds by decreasing their elongation at break.
  • the elastic modulus of the scaffolds with aligned assembly is four to five times higher than those with random fibrous assembly.
  • the pure PLLA scaffold with aligned assembly has much higher toughness but lower elongation at break than those with a random assembly. In the case of HA/PLLA scaffolds, such difference is not as significant as that of the pure PLLA scaffolds.
  • a homogenous apatite coating layer can also be formed on the surface of both PLLA and HA/PLLA scaffolds, as shown in FIGS. 8( a )-( b ).
  • the thickness of the coating is a few micrometers, which was obtained after approximately 4 hr of immersion in a modified simulated body fluid (m-SBF).
  • the thickness of the coating can be adjusted by varying the Ca and P ion concentrations in SBF, sample immersion time, and pH of the solution.
  • maintaining the immersion time short is important in order to maintain the integrity of the polymer fibers.
  • some polymer fibers absorb water, which leads to the reduction of their mechanical properties.
  • the thickness of the coating can be adjusted by varying the coating conditions such as, the m-SBF pH, immersion time, and calcium and phosphorous concentrations.
  • fluorescein isothiocyanate labeled bovine serum albumin was incorporated into the biomimetic apatite coating formed on the surfaces of the scaffold, to study the drug release behaviors of the electrospun scaffolds.
  • the drug release profiles of the electrospun HA/PLLA fibrous scaffolds are shown in FIG. 9 .
  • the release of FITC-BSA from the biomimetic coating on the scaffold was studied for a time period of 8 weeks. Sustained release profiles have been observed for all scaffolds.
  • the scaffolds with nano-size HA particles (NHA) showed faster release profiles than those incorporated with micro-size HA particles (MHA).
  • the biomimetic coating formed on the electrospun scaffold can be an effective carrier for sustained release of proteins and/or drugs.
  • PLLA-based electrospun scaffolds with different HA particles were used for in vitro cell culture study. Rat osteosarcoma cell line ROS 17/2.8 was used.
  • FIG. 10 illustrates relative cell viability on different scaffolds. According to certain embodiments of the present invention, with the increase of the cell culture time, more cells were attached to the surface of the scaffold. Especially, more cells were found on the scaffolds incorporated with either nano- or micro-size HA particles than those on pure PLLA scaffold after 7 days of culture. After 10 days, such difference became much more significant.
  • the cell alkaline phosphatase (ALP) activities, an early marker of bone formation, on different scaffolds are shown in FIG. 11 .
  • ALP alkaline phosphatase
  • a thicker apatite coating was obtained for the HA/PLLA scaffolds than the pure PLLA scaffolds with the same SBF soaking time. This may be explained by the fact that some of the HA particles loaded in the PLLA fibers position themselves on the surfaces of the fibers and act as nucleation sites for the apatite coating growth. Also, according to certain embodiments of the present invention, the coating grew more effectively on the top surface than the interior for both pure PLLA and HA/PLLA scaffold.
  • HA/PLLA composite fibrous scaffolds that include micro-scale pores throughout the body of the scaffold owing to electrospinning are also within the scope of the present invention.
  • Such scaffolds include nanometer-size pores on the surface of fibers in the scaffold owing to an evaporation process of highly volatile solvent.
  • nanoporous surfaces on composite fibers in the scaffold not only contribute to better bonding between a fiber substrate and an HA coating applied through a biomimetic coating method, but also induce fast degradation of the composite fibers.
  • a pumping device in order to promote a more homogenous apatite coating throughout the scaffold, is used to assist m-SBF penetrating into the scaffold or to create relatively large pores in the scaffold. Pores in the range of hundreds of micrometers, according to certain embodiments of the present invention, are desirable for both the invasion of blood vessels to provide the necessary nutrient supply to the transplanted cells and the bone formation.
  • HA/PLLA composite fibrous scaffolds that include at least one composite fiber surface and an HA coating on the composite fiber surface.
  • the coating is formed by using a biomimetic coating method.
  • the obtained HA coating layer on the fiber surface will typically not only increase the HA component within the scaffold and contribute to improved mechanical properties of the scaffold, but will also increase the exposure of HA to the surrounding tissue during in vivo application. Such exposure can improve the biocompatibility as well as the osteoconductivity of the composite scaffold.
  • a HA/PLLA composite fibrous scaffold that includes poly-lactic-co-glycolic acid (PLGA) microspheres incorporated among fibers.
  • PLGA poly-lactic-co-glycolic acid
  • the size of the microspheres is controlled to be above 100 micrometers. This typically not only increases the mechanical properties of the fibrous scaffold but may also be used as a carrier for releasing one or more different drugs.
  • a method of multi-drug delivery may be implemented. For example, two or more different drugs may be preloaded into different components of an electrospinning composite dope and PLGA microspheres to form a composite fibrous scaffold. Then, the drugs may be subsequently controllably released.

Abstract

An artificial bone composite structure is provided. This structure includes a fibrous matrix that itself includes a plurality of fibers. Also, the structure includes a plurality of hydroxyapatite (HA) particles. These particles are dispersed within the fibrous matrix. Also, the HA particles have controlled size and aspect ratios and are aligned along long axes of the fibers. In some instances, the fibers include poly-(L-lactic acid) (PLLA).

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of U.S. patent application entitled “Electrospan Apatite/Polymer Nano-Composite Scaffolds,” filed Mar. 26, 2008, having Ser. No. 12/055,865, and claims priority to provisional U.S. patent application entitled, “Electrospun Apatite/Polymer Nano-Composite Scaffolds,” filed Mar. 26, 2007, having Ser. No. 60/907,207, the disclosures of which are hereby incorporated by reference in their entirety.
  • FIELD OF THE INVENTION
  • The present invention relates generally to composite materials. The present invention also relates generally to methods of making composite materials.
  • BACKGROUND OF THE INVENTION
  • One prominent area of current scientific research in the medical field is focused upon artificially replicating human bones and other types of tissues. One of the goals of such research is to provide surgeons with artificially fabricated materials that may then be incorporated into a human patient during surgery.
  • Currently, some surgeons remove bone or tissues from one portion of a patient's body and reattach the bone or tissues in another portion of the patient's body. For example, during spinal surgery, bone from the hip is sometimes removed and incorporated into the spine. Some other surgeons are forced to incorporate metal components (e.g., metal rods and/or plates) in portions of a patient's body where natural bone has been shattered or has deteriorated.
  • Structurally, natural bone is a composite material that includes hydroxyapatite (HA) and fibrous collagen. In natural bone, the HA crystals are embedded within the collagen fiber matrix and are aligned along the long axis of fibers.
  • Currently, no method exists for artificially replicating the exact structure of natural bone. Even the most advanced methods for artificially replicate natural bone structure have at least been unsuccessful in aligning HA crystals in a manner analogous to the alignment in natural bone. As such, artificially generated bone does not have the same mechanical/biological/chemical properties as naturally occurring bone.
  • SUMMARY OF THE INVENTION
  • According to certain embodiments of the present invention, an apatite/fibrous polymer nano-composite scaffold has been fabricated using electrospinning Electrospinning is a convenient and versatile fabrication technique which produces fibers with diameters from approximately 50 nm to several micrometers. According to certain embodiments of the present invention, the structure generated by electrospinning is highly porous with interconnected pores. This fibrous structure typically resembles the architecture of an extracellular matrix (ECM). These fibrous structures may be used as artificial bone composite. Furthermore, these fibrous structures may be used with other tissues based on biocompatibility, mechanical properties, and cell attachment and growth of the fibrous structures and the tissues.
  • According to certain other embodiments of the present invention, HA particles with sizes ranging from approximately 10 nm to approximately 10 μm and having an average aspect ratio up to approximately 50 are synthesized. The HA particles are well dispersed in the spinning dope and co-electrospun with polymer nanofibers. The HA/PLLA nano-composite fibrous scaffold can be fabricated with HA particles homogenously distributed within the PLLA nanofibers.
  • According to still other embodiments of the present invention, up to approximately 20 wt % of HA nanoparticles is incorporated into the PLLA nanofibers. These nanoparticles are well aligned along the long axes of the polymer fibers. Such obtained microstructure closely mimics the micro-arrangement of the inorganic/organic components in the ECM of natural bone. Such fabricated scaffolds have desirable mechanical properties and good cell signaling properties. At least in view of the above, such scaffolds are suitable for loading cells and biological active agents. It should also be noted that incorporation of more than 20 wt % HA nanoparticles is also within the scope of certain embodiments of the present invention.
  • It is desirable to fabricate bone graft materials mimicking the structural, mechanical, and biological behavior of natural bone. This need is met, to a great extent, by certain embodiments of the present invention, particularly those wherein a structure is provided that includes a scaffold and highly crystallized, well-dispersed HA nanoparticles. In this structure, the HA nanoparticles have controllable aspect ratios within the range of approximately 5 and approximately 50.
  • According to other embodiments of the present invention, a structure is provided that includes a fibrous matrix that itself includes a plurality of fibers. The structure also includes a plurality of hydroxyapatite (HA) particles dispersed within the fibrous matrix, wherein the HA particles are substantially aligned along long axes of the plurality of fibers.
  • According to yet other embodiments of the present invention, a method of forming a structure is provided. The method includes adding hydroxyapatite (HA) particles to a poly-(L-lactic acid) (PLLA) solution to form a mixture and forming an HA/PLLA fiber by electrospinning the mixture.
  • According to still other embodiments of the present invention, a structure is provided that includes a fibrous matrix including a plurality of fibers. The structure also includes a plurality of hydroxyapatite (HA) particles dispersed within the fibrous matrix, wherein the HA particles are substantially aligned along long axes of the plurality of fibers, wherein the structure is manufactured by adding the HA particles to a poly-(L-lactic acid) (PLLA) solution to form a mixture and by forming HA/PLLA fibers by electrospinning the mixture to form the fibrous matrix.
  • There has thus been outlined, rather broadly, certain embodiments of the invention in order that the detailed description thereof may be better understood, and in order that the present contribution to the art may be better appreciated. There are, of course, additional embodiments of the invention that will be described below and which will form the subject matter of the claims appended hereto.
  • In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of embodiments in addition to those described and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein, as well as the abstract, are for the purpose of description and should not be regarded as limiting.
  • As such, those skilled in the art will appreciate that the conception upon which this disclosure is based may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.
  • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIGS. 1( a)-(c) illustrate morphologies of electrospun PLLA and HA/PLLA composite nanofibers. More specifically, FIG. 1( a) illustrates a field emission scanning electron microscope (FESEM) image of electrospun PLLA nanofibers, FIG. 1( b) illustrates an FESEM image of HA/PLLA (20:80 w/w) composite nanofibers, and FIG. 1( c) illustrates a transmission electron microscope (TEM) image of HA/PLLA/HA (20:80 w/w) composite nanofibers.
  • FIGS. 2( a)-(f) illustrate the effect of varying various electrospinning parameters. FIG. 2( a) illustrates the effect of varying PLLA concentration in the electrospinning dope. FIG. 2( b) illustrates the effect of varying the amount of HA incorporation (wt %) in the composite fibers. FIG. 2( c) illustrates the effect of varying power voltage. FIG. 2( d) illustrates the effect of varying the injection rate. FIG. 2( e) illustrates the effect of varying the spinneret inner diameter. FIG. 2( f) illustrates the effect of varying the distance between the spinneret tip and the collector on the diameter of the electrospun nanofibers.
  • FIGS. 3( a)-(c) illustrate functionalized PLLA fibers. FIG. 3( a) is a TEM image of polyethylene glycol (PEG)-core-PLLA-shell nanofibers. FIG. 3( b) is an FESEM image of highly aligned PLLA nano fibers. FIG. 3( c) is an FESEM image of highly porous PLLA nano fibers.
  • FIGS. 4( a)-(c) illustrate the mechanical properties of electrospun PLLA and HA/PLLA scaffolds. FIG. 4( a) illustrates typical stress v. strain curves for HA/PLLA electrospun scafolds with an averaged fiber diameters equal to 110±15 nm. FIG. 4( b) illustrates Young's moduli (E, hatched bars) and tensile stresses (solid bars) of HA/PLLA electrospun scaffolds with averaged fiber diameters equal to 110±15 nm. FIG. 4( c) illustrates Young's moduli (E) and tensile stresses of different component HA/PLLA electrospun scaffolds with averaged fiber diameters equal to 170±25 nm.
  • FIGS. 5( a) and (b) illustrate the mechanical properties of electrospun fibrous scaffolds with different compositions and fibrous assemblies. FIG. 5( a) illustrates the stress vs. strain curves for electrospun fibrous scaffolds with different compositions and fibrous assemblies. FIG. 5( b) illustrates the tensile test results for electrospun fibrous scaffolds with different compositions and fibrous assemblies.
  • FIGS. 6( a)-(e) illustrate PLLA nanofibers obtained from electrospinning according to certain embodiments of the present invention. FIG. 6( a) illustrates the average diameters and standard variations for fibers electrospun from different PLLA concentrations. The concentration used in FIG. 6( b) was PLLA=4.0 wt %. The concentration used in FIG. 6( c) was PLLA=6.0 wt %. The concentration used in FIG. 6( d) was PLLA=8.0 wt %. The concentration used in FIG. 6( e) was PLLA=10.0 wt %. FIG. 6( b)-(e) were all taken at a magnification of ×20,000.
  • FIGS. 7( a)-(d) illustrate electrospun HA/PLLA composites. The HA particles in the composite were synthesized via a metathesis reaction at 100° C. in FIG. 6( a), via a metathesis reaction at 70° C. in FIG. 7( b), via a metathesis reaction at 95° C. in FIG. 7( c), and via a urea decomposition at 95° C. in FIG. 7( d). One of skill in the art will recognize that HA particles with different sizes and aspect ratios are evenly distributed within the illustrated polymer nanofibers. Also, the composites illustrated in FIGS. 7( a)-(d) demonstrate a good orientation along the long axis of the PLA nanofibers. The HA content in these composites are 20 wt %.
  • FIGS. 8( a)-(b) illustrate thin layers of a biomimetic apatite coating on the surface of PLLA and HA/PLLA scaffolds, respectively.
  • FIG. 9 illustrates in vitro release of FITC-BSA from electrospun HA/PLLA fibrous scaffold with needle-shape HA particles either at nano-(NHA) or microsize (MHA) and with either random or aligned fibrous assembly.
  • FIG. 10 illustrates relative cell viability on different scaffolds after being cultured for 3, 7, and 10 days. (Sample A) PLLA scaffold with random assembly, (Sample B) micrometer-size HA/PLLA scaffold with random assembly, (Sample C) nanometer-size HA/PLLA scaffold with random assembly, (Sample D) biomimetic apatite-coated nanometer-size HA/PLLA scaffold with random assembly, (Sample E) micrometer-size HA/PLLA scaffold with aligned assembly, and (Sample F) nanometer-size HA/PLLA scaffold with aligned assembly.
  • FIG. 11 illustrates relative alkaline phosphatase (ALP) activities on different scaffolds after being cultured for 7 and 10 days. (Sample A) PLLA scaffold with random assembly, (Sample B) micrometer-size HA/PLLA scaffold with random assembly, (Sample C) nanometer-size HA/PLLA scaffold with random assembly, (Sample D) biomimetic apatite-coated nanometer-size HA/PLLA scaffold with random assembly, (Sample E) micrometer-size HA/PLLA scaffold with aligned assembly, and (Sample F) nanometer-size HA/PLLA scaffold with aligned assembly.
  • DETAILED DESCRIPTION
  • The invention will now be described with reference to the drawing figures, in which like reference numerals refer to like parts throughout. According to certain embodiments of the present invention, HA/PLLA composite scaffolds are electrospun. However, it should be noted that other composite systems using materials other than HA and PLLA are also within the scope of certain embodiments of the present invention. For example, collagen, hyaluronans, fibrin, chitosan, alginate, other animal- or plant-derived polymers, PLA, PCL, PGA, other synthetic and natural polymers, polyesters, polyethers, polycarbonates, polyamines, polyamides, and their co-polymers and combinations may be used. Also, for example, carbonated HA, and other calcium phosphates (e.g., ion-substituted apatites, such as carbonate hydroxyapatite, fluorinated hydroxyapatite, chlorinated hydroxyapatite, silicon-containing hydroxyapatite, magnesium-containing hydroxyapatite and other ion substituted HA, tricalcium phosphate, tetracalcium phosphate, monetite, dicalcium phosphate, dicalcium phosphate dihydrate, octacalcium phosphate, or calcium sulfate) may also be used. The effect of the processing parameters on fiber diameter has been carefully studied and the polymer molecular weight and dope concentration greatly affected fiber diameters ranging from 50 nm to 500 nm.
  • In order to fabricate the above-discussed scaffolds, HA particles were added to a PLLA solution to fabricate an HA/PLLA composite. Also, the amount of HA in the PLLA solution was adjusted by varying the HA to PLLA feeding ratio in the spin-dope.
  • According to certain embodiments of the present invention, up to approximately 20 wt % of HA is incorporated into PLLA nanofibers. These HA particles are typically well aligned along the long axis of the polymer fibers. The size of the HA particles have an average width of at least 10 nm and an average length ranged from approximately 10 nm to approximately 10 μm, with an average aspect ratio up to approximately 50. The particles, according to certain embodiments of the present invention, were homogenously distributed within the PLLA nanofibers after electrospinning The resultant microstructure closely mimicked the arrangement of the inorganic/organic components in ECM of natural bone. Compared to the fibrous scaffold fabricated with pure PLLA, the HA/PLLA scaffold has improved mechanical properties and biocompatibility.
  • As illustrated in FIGS. 1( a)-(c), HA particles with lengths between 100 and 200 nm and aspect ratios between 7 and 10 were evenly distributed within HA/PLLA fiber bodies. These particles also demonstrated a good orientation along the long axes of the PLLA nanofibers.
  • The effects of altering the electrospinning processing parameters on the diameter of HA/PLLA composite fibers were studied in FIG. 2. As illustrated, varying the polymer concentration of the electrospinning dope and varying the HA/PLLA weight ratio have the most obvious influences on the diameter. As illustrated in FIG. 2( a), the diameter of composite nanofibers increase with the PLLA concentration in the spinning dope, which indicates that a high PLLA concentration dope has higher surface tension and was more difficult to be spun into finer fibers during the fiber spinning process. FIG. 2( b) illustrates that composite fiber diameter decreases with increasing HA weight ratio. This is likely explained by the fact that higher amounts of HA in a composite decreases the viscosity of the electrospinning dope and the surface tension thereof as well.
  • As illustrated in FIG. 3, several modified electrospinning techniques for fabricating functionalized nanofibrous scaffolds have been implemented according to various embodiments of the present invention. First, a PEG/PLLA core-shell structure has been co-electrospun into a fibrous composite scaffold using co-axial dual spinnerets, as shown in FIG. 3( a). Second, highly aligned nanofibers were fabricated using a rotating drum as the collector, as illustrated in FIG. 3( b). Scaffolds prepared in this manner have good orientation and improved mechanical strength along the long axes of the fibers. Third, nanofibers with a porous surface have been electrospun using a mixture of CH2Cl2 (DCM) and DMF (DCM/DMF=6/1 (v/v)) as a solvent, as illustrated in FIG. 3( c).
  • As illustrated in FIG. 3, the porosity and pore size of fibers according to certain embodiments of the present invention can be adjusted by altering the solvent used and dope concentration. The porous surface of the fibers can be used, for example, for controlled delivery of growth factors. Moreover, the porous surface will also enhance the bonding strength between the polymer fiber and a biomimetic apatite coating, such as the one illustrated in FIG. 8( b). The porous surface may also act as a nucleation site for apatite further growth.
  • FIG. 4 compares mechanical properties of various electrospun composite fibers with different HA incorporation ratios. One of skill in the art will recognize, upon analyzing FIGS. 4( a)-(c), that both the Young's moduli and tensile stresses of the electrospun mats increased continuously as the HA incorporation ratio increased. This can be explained by the fact that HA, when well dispersed and aligned along fiber long axes, plays a substantial role in reinforcing the composite fibrous mat. Comparisons between the data included in FIG. 4( b) and FIG. 4( c) also demonstrates that fibrous mats with thicker composite nanofibers present more desirable mechanical properties.
  • FIG. 5( a)-(b) illustrates the mechanical properties of electrospun PLLA-based scaffolds using tensile test. One of skill in the art will recognize that both the alignment of the scaffold assembly and the incorporation of nano-size, needle-shape HA particles into the nano-fibers significantly improved the elastic modulus of the composite scaffold. The scaffold with HA particles are much stiffer than those without HA particles, and the elastic modulus of the former is more than two times as high as that of the later. It is also shown that, the HA nanoparticles inhibit un-folding and orientation of PLLA molecular chains within spun fibers during tensile testing, i.e. cold drawing of the scaffold, and decrease the toughness of the composite scaffolds by decreasing their elongation at break.
  • According to certain embodiments of the presentation, the elastic modulus of the scaffolds with aligned assembly is four to five times higher than those with random fibrous assembly. Moreover, the pure PLLA scaffold with aligned assembly has much higher toughness but lower elongation at break than those with a random assembly. In the case of HA/PLLA scaffolds, such difference is not as significant as that of the pure PLLA scaffolds.
  • According to certain embodiments of the present invention, a homogenous apatite coating layer can also be formed on the surface of both PLLA and HA/PLLA scaffolds, as shown in FIGS. 8( a)-(b). The thickness of the coating is a few micrometers, which was obtained after approximately 4 hr of immersion in a modified simulated body fluid (m-SBF). The thickness of the coating can be adjusted by varying the Ca and P ion concentrations in SBF, sample immersion time, and pH of the solution.
  • According to certain embodiments of the present invention, maintaining the immersion time short is important in order to maintain the integrity of the polymer fibers. According to some of these embodiments, some polymer fibers absorb water, which leads to the reduction of their mechanical properties. Nevertheless, the thickness of the coating can be adjusted by varying the coating conditions such as, the m-SBF pH, immersion time, and calcium and phosphorous concentrations.
  • According to certain embodiments of the present invention, fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) was incorporated into the biomimetic apatite coating formed on the surfaces of the scaffold, to study the drug release behaviors of the electrospun scaffolds. The drug release profiles of the electrospun HA/PLLA fibrous scaffolds are shown in FIG. 9. The release of FITC-BSA from the biomimetic coating on the scaffold was studied for a time period of 8 weeks. Sustained release profiles have been observed for all scaffolds. The scaffolds with nano-size HA particles (NHA) showed faster release profiles than those incorporated with micro-size HA particles (MHA). Also, a slightly faster release has been observed for the scaffolds with an aligned assembly than those with a random assembly. According to certain embodiments of the present invention, the biomimetic coating formed on the electrospun scaffold can be an effective carrier for sustained release of proteins and/or drugs.
  • According to certain embodiments of the present invention, PLLA-based electrospun scaffolds with different HA particles were used for in vitro cell culture study. Rat osteosarcoma cell line ROS 17/2.8 was used. FIG. 10 illustrates relative cell viability on different scaffolds. According to certain embodiments of the present invention, with the increase of the cell culture time, more cells were attached to the surface of the scaffold. Especially, more cells were found on the scaffolds incorporated with either nano- or micro-size HA particles than those on pure PLLA scaffold after 7 days of culture. After 10 days, such difference became much more significant.
  • According to certain embodiments of the present invention, the cell alkaline phosphatase (ALP) activities, an early marker of bone formation, on different scaffolds are shown in FIG. 11. According to certain embodiments of the present invention, after 10 days of culture, almost all the HA incorporated scaffolds showed significantly higher ALP activities than the control, pure PLLA scaffold. These results collectively suggested that hydroxyapatite has improved the biocompatibility and cell signaling properties of the scaffold, which could make the scaffold a better material for bone fracture repair.
  • According to certain embodiments of the present invention, a thicker apatite coating was obtained for the HA/PLLA scaffolds than the pure PLLA scaffolds with the same SBF soaking time. This may be explained by the fact that some of the HA particles loaded in the PLLA fibers position themselves on the surfaces of the fibers and act as nucleation sites for the apatite coating growth. Also, according to certain embodiments of the present invention, the coating grew more effectively on the top surface than the interior for both pure PLLA and HA/PLLA scaffold.
  • HA/PLLA composite fibrous scaffolds that include micro-scale pores throughout the body of the scaffold owing to electrospinning are also within the scope of the present invention. Such scaffolds, according to certain embodiments of the present invention, include nanometer-size pores on the surface of fibers in the scaffold owing to an evaporation process of highly volatile solvent. In such embodiments, nanoporous surfaces on composite fibers in the scaffold not only contribute to better bonding between a fiber substrate and an HA coating applied through a biomimetic coating method, but also induce fast degradation of the composite fibers.
  • According to certain embodiments of the present invention, in order to promote a more homogenous apatite coating throughout the scaffold, a pumping device is used to assist m-SBF penetrating into the scaffold or to create relatively large pores in the scaffold. Pores in the range of hundreds of micrometers, according to certain embodiments of the present invention, are desirable for both the invasion of blood vessels to provide the necessary nutrient supply to the transplanted cells and the bone formation.
  • Other embodiments of the present invention include HA/PLLA composite fibrous scaffolds that include at least one composite fiber surface and an HA coating on the composite fiber surface. According to some of these embodiments, the coating is formed by using a biomimetic coating method. Also, the obtained HA coating layer on the fiber surface will typically not only increase the HA component within the scaffold and contribute to improved mechanical properties of the scaffold, but will also increase the exposure of HA to the surrounding tissue during in vivo application. Such exposure can improve the biocompatibility as well as the osteoconductivity of the composite scaffold.
  • Also according to certain embodiments of the present invention, a HA/PLLA composite fibrous scaffold is provided that includes poly-lactic-co-glycolic acid (PLGA) microspheres incorporated among fibers. According to some of these embodiments, the size of the microspheres is controlled to be above 100 micrometers. This typically not only increases the mechanical properties of the fibrous scaffold but may also be used as a carrier for releasing one or more different drugs.
  • Using scaffolds such as the ones discussed above, a method of multi-drug delivery may be implemented. For example, two or more different drugs may be preloaded into different components of an electrospinning composite dope and PLGA microspheres to form a composite fibrous scaffold. Then, the drugs may be subsequently controllably released.
  • The many features and advantages of the invention are apparent from the detailed specification, and thus, it is intended by the appended claims to cover all such features and advantages of the invention which fall within the true spirit and scope of the invention. Further, since numerous modifications and variations will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation illustrated and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.

Claims (10)

1. A method of forming a bone composite structure, the method comprising:
adding hydroxyapatite (HA) particles to a poly-(L-lactic acid) (PLLA) solution to form a mixture; and
forming an HA/PLLA fiber by electrospinning the mixture.
2. The method of claim 1, wherein the forming step comprises the fiber to have a diameter of between approximately 50 nm and several micrometers.
3. The method of claim 1, further comprising:
forming the HA particles to be sized between approximately 10 nm and approximately 10 micrometers.
4. The method of claim 1, further comprising:
forming the HA particles to have aspect ratios of between approximately 5 and approximately 50.
5. The method of claim 1, wherein the forming step comprises:
utilizing substantially co-axial dual spinnerets during the electrospinning of the mixture.
6. The method of claim 1, wherein the forming step comprises: utilizing a rotating drum as a collector during the electrospinning of the mixture.
7. The method of claim 1, further comprising:
immersing the fiber in a modified simulated body fluid (m-SBF) solution.
8. The method of claim 7, further comprising:
pumping the m-SBF through a pumping device during the immersing step.
9. The method of claim 7, further comprising:
creat large pores by electrospinning to enhance mass transfer in the structure.
10. The method of claim 1, further comprising:
incorporating poly-lactic-co-glycolic acid (PLGA) microspheres among the plurality of fibers.
US12/971,235 2007-03-26 2010-12-17 Electrospun Apatite/Polymer Nano-Composite Scaffolds Abandoned US20110140295A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/971,235 US20110140295A1 (en) 2007-03-26 2010-12-17 Electrospun Apatite/Polymer Nano-Composite Scaffolds

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US90720707P 2007-03-26 2007-03-26
US12/055,865 US7879093B2 (en) 2007-03-26 2008-03-26 Electrospun apatite/polymer nano-composite scaffolds
US12/971,235 US20110140295A1 (en) 2007-03-26 2010-12-17 Electrospun Apatite/Polymer Nano-Composite Scaffolds

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US12/055,865 Division US7879093B2 (en) 2007-03-26 2008-03-26 Electrospun apatite/polymer nano-composite scaffolds

Publications (1)

Publication Number Publication Date
US20110140295A1 true US20110140295A1 (en) 2011-06-16

Family

ID=39789007

Family Applications (2)

Application Number Title Priority Date Filing Date
US12/055,865 Expired - Fee Related US7879093B2 (en) 2007-03-26 2008-03-26 Electrospun apatite/polymer nano-composite scaffolds
US12/971,235 Abandoned US20110140295A1 (en) 2007-03-26 2010-12-17 Electrospun Apatite/Polymer Nano-Composite Scaffolds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US12/055,865 Expired - Fee Related US7879093B2 (en) 2007-03-26 2008-03-26 Electrospun apatite/polymer nano-composite scaffolds

Country Status (6)

Country Link
US (2) US7879093B2 (en)
EP (1) EP2129517A4 (en)
JP (1) JP2010522620A (en)
CN (1) CN101687384A (en)
CA (1) CA2680586A1 (en)
WO (1) WO2008118943A1 (en)

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008106625A2 (en) 2007-02-28 2008-09-04 University Of Notre Dame Du Lac Porous composite biomaterials and related methods
US11179243B2 (en) 2007-02-28 2021-11-23 Happe Spine Llc Implantable devices
US9149563B2 (en) * 2007-11-06 2015-10-06 The University Of Connecticut Calcium phosphate/structural protein composites and method of preparation thereof
WO2009061887A2 (en) * 2007-11-06 2009-05-14 University Of Connecticut Ceramic/structural protein composites and method of preparation thereof
US9402724B2 (en) * 2008-05-12 2016-08-02 Mo-Sci Corporation Dynamic bioactive nanofiber scaffolding
KR101265093B1 (en) * 2008-12-26 2013-05-16 한국과학기술연구원 Nano powder, nano ink and micro rod, and the fabrication method thereof
CA2965110C (en) 2010-06-17 2020-06-02 Washington University Biomedical patches with aligned fibers
CN107778528B (en) 2010-07-14 2021-06-15 密苏里大学学监 Polymer composites and their preparation
WO2012048188A1 (en) * 2010-10-07 2012-04-12 Drixel University Electrospun mineralized chitosan nanofibers crosslinked with genipin for bone tissue enginering
WO2012129527A2 (en) * 2011-03-24 2012-09-27 Cornell University Biofunctional nanofibers for analyte separation in microchannels
US10081794B2 (en) * 2011-04-13 2018-09-25 New Jersey Institute Of Technology System and method for electrospun biodegradable scaffold for bone repair
US20160000974A1 (en) * 2011-08-09 2016-01-07 New Jersey Institute Of Technoloty Composite Matrix for Bone Repair Applications
US20150230918A1 (en) * 2011-08-16 2015-08-20 The University Of Kansas Biomaterial based on aligned fibers, arranged in a gradient interface, with mechanical reinforcement for tracheal regeneration and repair
CN102389395A (en) * 2011-11-07 2012-03-28 东华大学 Preparation of n-HA/PLGA electrostatic spinning composite nanofiber medicament loading system
CN102499997A (en) * 2011-12-27 2012-06-20 吉林大学 Composite nano fiber support material, as well as preparation method and application in bone repairing aspect
US9078832B2 (en) 2012-03-22 2015-07-14 The University Of Connecticut Biomimetic scaffold for bone regeneration
KR20150015532A (en) * 2012-05-30 2015-02-10 뉴욕 유니버시티 Tissue repair devices and scaffolds
CN102677226B (en) * 2012-06-05 2014-05-28 东华大学 Preparation method of organic-inorganic hybrid electrostatic spinning nano drug-loaded fiber
KR101998410B1 (en) * 2012-08-22 2019-07-09 가톨릭대학교 산학협력단 Scaffolds having double layer structure with gradient mineral concentration for tissue regeneration and preparation method thereof
KR102178233B1 (en) 2012-09-21 2020-11-12 워싱톤 유니버시티 Biomedical patches with spatially arranged fibers
EP3275472B1 (en) * 2013-07-09 2019-01-09 National University Corporation Nagoya Institute of Technology Bone defect filling material, and production method therefor
CN103585635A (en) * 2013-10-31 2014-02-19 江苏大学 Slow-release polylactic acid microsphere capable of maintaining protein and polypeptide drug activity and preparation method thereof
CA2882468A1 (en) 2014-02-19 2015-08-19 Samin Eftekhari Artificial bone nanocomposite and method of manufacture
US9895354B2 (en) * 2014-04-04 2018-02-20 University Of Kentucky Research Foundation Bilayered calcium sulfate/calcium phosphate space-making composites with multiple drug delivery capabilities
US11058521B2 (en) 2014-08-18 2021-07-13 University of Central Oklahoma Method and apparatus for improving osseointegration, functional load, and overall strength of intraosseous implants
US10932910B2 (en) 2014-08-18 2021-03-02 University of Central Oklahoma Nanofiber coating to improve biological and mechanical performance of joint prosthesis
CN104264368B (en) * 2014-09-23 2016-07-13 杭州同净环境科技有限公司 A kind of preparation method of the spontaneous type microorganism attachment fiber that is separated
LT6309B (en) 2014-10-13 2016-08-25 Uab "Biomė" Porous three dimensional cellulose based scaffold and method
CN104815355B (en) * 2015-04-16 2017-08-25 四川大学 Surface has hydroxyapatite/polyamide composite biological material of nanofiber loose structure and preparation method thereof
CA3055171C (en) * 2016-03-23 2021-07-27 University of Central Oklahoma Method and apparatus to coat a metal implant with electrospun nanofiber matrix
US10632228B2 (en) 2016-05-12 2020-04-28 Acera Surgical, Inc. Tissue substitute materials and methods for tissue repair
RU2624854C1 (en) * 2016-10-18 2017-07-07 Федеральное государственное автономное образовательное учреждение высшего образования "Национальный исследовательский Томский политехнический университет" Method for obtaining of composite scaffold for bone tissue defects restoration
CN106853264A (en) * 2016-11-10 2017-06-16 南京市口腔医院 Super-paramagnetism nano tunica fibrosa timbering material, preparation method and application
EP3595515A4 (en) 2017-03-14 2020-12-30 University of Connecticut Biodegradable pressure sensor
US11826495B2 (en) 2019-03-01 2023-11-28 University Of Connecticut Biodegradable piezoelectric ultrasonic transducer system
CN113811266A (en) 2019-03-12 2021-12-17 哈佩脊椎有限责任公司 Implantable medical device having a thermoplastic composite and method for forming a thermoplastic composite
RU2722452C1 (en) * 2019-08-28 2020-06-01 федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр травматологии и ортопедии имени академика Г.А. Илизарова" Министерства здравоохранения Российской Федерации Regenerative method of articular cartilage defect replacement
US11745001B2 (en) 2020-03-10 2023-09-05 University Of Connecticut Therapeutic bandage
CN111529759B (en) * 2020-04-23 2021-12-07 东华大学 Macroporous bone tissue engineering scaffold capable of sustainably releasing inorganic active ingredients and preparation method thereof
CN114231996B (en) * 2022-02-28 2022-05-31 青岛理工大学 Zinc molybdate-cobalt titanate coaxial fiber photo-anode film and preparation method and application thereof

Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4192021A (en) * 1976-05-12 1980-03-11 Batelle-Institut e.V. Bone replacement or prosthesis anchoring material
US4279249A (en) * 1978-10-20 1981-07-21 Agence Nationale De Valorisation De La Recherche (Anvar) New prosthesis parts, their preparation and their application
US4329743A (en) * 1979-04-27 1982-05-18 College Of Medicine And Dentistry Of New Jersey Bio-absorbable composite tissue scaffold
US4629464A (en) * 1984-09-25 1986-12-16 Tdk Corporation Porous hydroxyapatite material for artificial bone substitute
US4659617A (en) * 1984-09-11 1987-04-21 Toa Nenryo Kogyo Kabushiki Kaisha Fibrous apatite and method for producing the same
US4698375A (en) * 1985-02-19 1987-10-06 The Dow Chemical Company Composites of unsintered calcium phosphates and synthetic biodegradable polymers useful as hard tissue prosthetics
US4904257A (en) * 1986-03-20 1990-02-27 Toa Nenryo Kogyo K. K. Fibrous bone filler and process of producing the same
US4968317A (en) * 1987-01-13 1990-11-06 Toermaelae Pertti Surgical materials and devices
US5084051A (en) * 1986-11-03 1992-01-28 Toermaelae Pertti Layered surgical biocomposite material
US5092890A (en) * 1989-01-12 1992-03-03 Basf Aktiengesellschaft Implant materials for hard tissue
US5227147A (en) * 1990-11-20 1993-07-13 Mitsubishi Materials Corp. Apatite whisker and method for preparation thereof
US6027742A (en) * 1995-05-19 2000-02-22 Etex Corporation Bioresorbable ceramic composites
US6214008B1 (en) * 1997-04-16 2001-04-10 White Spot Ag Biodegradable osteosynthesis implant
US20030031698A1 (en) * 2000-01-31 2003-02-13 Roeder Ryan K. Composite biomaterial including anisometric calcium phosphate reinforcement particles and related methods
US20040037813A1 (en) * 1999-02-25 2004-02-26 Simpson David G. Electroprocessed collagen and tissue engineering
US20040137032A1 (en) * 2002-03-15 2004-07-15 Wang Francis W. Combinations of calcium phosphates, bone growth factors, and pore-forming additives as osteoconductive and osteoinductive composite bone grafts
US20050058632A1 (en) * 2001-12-07 2005-03-17 Hedrick Marc H. Cell carrier and cell carrier containment devices containing regenerative cells
US6887272B2 (en) * 2001-02-23 2005-05-03 Japan Science And Technology Agency Artificial pyramid
US6887488B2 (en) * 2000-05-19 2005-05-03 Tsinghua University Nano-calcium phosphates/collagen based bone substitute materials
US20050142162A1 (en) * 2003-11-20 2005-06-30 Angiotech International Ag Soft tissue implants and anti-scarring agents
US20050147643A1 (en) * 2003-11-10 2005-07-07 Angiotech International Ag Medical implants and fibrosis-inducing agents
US20050255779A1 (en) * 2004-04-22 2005-11-17 Ngk Spark Plug Co., Ltd. Organic-inorganic composite porous material, method for producing fibrous organic material, and method for producing organic-inorganic composite porous material
US20060067969A1 (en) * 2004-03-05 2006-03-30 Lu Helen H Multi-phased, biodegradable and osteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone
US20060154063A1 (en) * 2004-12-15 2006-07-13 Kazutoshi Fujihara Nanofiber construct and method of preparing thereof
US20060199876A1 (en) * 2005-03-04 2006-09-07 The University Of British Columbia Bioceramic composite coatings and process for making same
US20060204539A1 (en) * 2005-03-11 2006-09-14 Anthony Atala Electrospun cell matrices
US20060257377A1 (en) * 2005-03-11 2006-11-16 Wake Forest University Health Services Production of tissue engineered digits and limbs
US20070041952A1 (en) * 2005-04-18 2007-02-22 Duke University Three-dimensional fiber scaffolds for tissue engineering
US20070132155A1 (en) * 2005-12-13 2007-06-14 Robert Burgermeister Polymeric stent having modified molecular structures in selected regions of the hoops and method for increasing elongation at break
US20070141333A1 (en) * 2004-03-25 2007-06-21 Shastri Venkatram P Emulsion-based control of electrospun fiber morphology
US20070225631A1 (en) * 2002-10-04 2007-09-27 Bowlin Gary L Sealants for Skin and Other Tissues
US20070256422A1 (en) * 2006-05-08 2007-11-08 Econo-Power International Corporation Production enhancements on integrated gasification combined cycle power plants
US20080112998A1 (en) * 2006-11-14 2008-05-15 Hongjun Wang Innovative bottom-up cell assembly approach to three-dimensional tissue formation using nano-or micro-fibers
US20080220054A1 (en) * 2006-10-13 2008-09-11 Shastri V Prasad Modulation of drug release rate from electrospun fibers
US20090317446A1 (en) * 2006-09-01 2009-12-24 Cornell Research Foundation, Inc. Calcium Phosphate Nanofibers

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006036130A1 (en) 2004-09-29 2006-04-06 National University Of Singapore A composite, method of producing the composite and uses of the same
US8871237B2 (en) * 2005-04-04 2014-10-28 Technion Research & Development Foundation Limited Medical scaffold, methods of fabrication and using thereof
US8932620B2 (en) 2005-06-17 2015-01-13 Drexel University Three-dimensional scaffolds for tissue engineering made by processing complex extracts of natural extracellular matrices
KR100785378B1 (en) * 2005-09-05 2007-12-14 주식회사 바이오레인 Multi-layered antiadhesion barrier
EP2010104B1 (en) * 2006-04-25 2018-09-05 Teleflex Medical Incorporated Calcium phosphate polymer composite and method

Patent Citations (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4192021A (en) * 1976-05-12 1980-03-11 Batelle-Institut e.V. Bone replacement or prosthesis anchoring material
US4279249A (en) * 1978-10-20 1981-07-21 Agence Nationale De Valorisation De La Recherche (Anvar) New prosthesis parts, their preparation and their application
US4329743A (en) * 1979-04-27 1982-05-18 College Of Medicine And Dentistry Of New Jersey Bio-absorbable composite tissue scaffold
US4659617A (en) * 1984-09-11 1987-04-21 Toa Nenryo Kogyo Kabushiki Kaisha Fibrous apatite and method for producing the same
US4629464A (en) * 1984-09-25 1986-12-16 Tdk Corporation Porous hydroxyapatite material for artificial bone substitute
US4698375A (en) * 1985-02-19 1987-10-06 The Dow Chemical Company Composites of unsintered calcium phosphates and synthetic biodegradable polymers useful as hard tissue prosthetics
US4904257A (en) * 1986-03-20 1990-02-27 Toa Nenryo Kogyo K. K. Fibrous bone filler and process of producing the same
US5084051A (en) * 1986-11-03 1992-01-28 Toermaelae Pertti Layered surgical biocomposite material
US4968317A (en) * 1987-01-13 1990-11-06 Toermaelae Pertti Surgical materials and devices
US4968317B1 (en) * 1987-01-13 1999-01-05 Biocon Oy Surgical materials and devices
US5092890A (en) * 1989-01-12 1992-03-03 Basf Aktiengesellschaft Implant materials for hard tissue
US5227147A (en) * 1990-11-20 1993-07-13 Mitsubishi Materials Corp. Apatite whisker and method for preparation thereof
US6027742A (en) * 1995-05-19 2000-02-22 Etex Corporation Bioresorbable ceramic composites
US6214008B1 (en) * 1997-04-16 2001-04-10 White Spot Ag Biodegradable osteosynthesis implant
US20040037813A1 (en) * 1999-02-25 2004-02-26 Simpson David G. Electroprocessed collagen and tissue engineering
US20030031698A1 (en) * 2000-01-31 2003-02-13 Roeder Ryan K. Composite biomaterial including anisometric calcium phosphate reinforcement particles and related methods
US7758882B2 (en) * 2000-01-31 2010-07-20 Indiana University Research And Technology Corporation Composite biomaterial including anisometric calcium phosphate reinforcement particles and related methods
US6887488B2 (en) * 2000-05-19 2005-05-03 Tsinghua University Nano-calcium phosphates/collagen based bone substitute materials
US6887272B2 (en) * 2001-02-23 2005-05-03 Japan Science And Technology Agency Artificial pyramid
US20050058632A1 (en) * 2001-12-07 2005-03-17 Hedrick Marc H. Cell carrier and cell carrier containment devices containing regenerative cells
US20040137032A1 (en) * 2002-03-15 2004-07-15 Wang Francis W. Combinations of calcium phosphates, bone growth factors, and pore-forming additives as osteoconductive and osteoinductive composite bone grafts
US20070225631A1 (en) * 2002-10-04 2007-09-27 Bowlin Gary L Sealants for Skin and Other Tissues
US20050147643A1 (en) * 2003-11-10 2005-07-07 Angiotech International Ag Medical implants and fibrosis-inducing agents
US20050142162A1 (en) * 2003-11-20 2005-06-30 Angiotech International Ag Soft tissue implants and anti-scarring agents
US20060067969A1 (en) * 2004-03-05 2006-03-30 Lu Helen H Multi-phased, biodegradable and osteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone
US20070141333A1 (en) * 2004-03-25 2007-06-21 Shastri Venkatram P Emulsion-based control of electrospun fiber morphology
US20050255779A1 (en) * 2004-04-22 2005-11-17 Ngk Spark Plug Co., Ltd. Organic-inorganic composite porous material, method for producing fibrous organic material, and method for producing organic-inorganic composite porous material
US20060154063A1 (en) * 2004-12-15 2006-07-13 Kazutoshi Fujihara Nanofiber construct and method of preparing thereof
US20060199876A1 (en) * 2005-03-04 2006-09-07 The University Of British Columbia Bioceramic composite coatings and process for making same
US20060204539A1 (en) * 2005-03-11 2006-09-14 Anthony Atala Electrospun cell matrices
US20060257377A1 (en) * 2005-03-11 2006-11-16 Wake Forest University Health Services Production of tissue engineered digits and limbs
US20070041952A1 (en) * 2005-04-18 2007-02-22 Duke University Three-dimensional fiber scaffolds for tissue engineering
US20070132155A1 (en) * 2005-12-13 2007-06-14 Robert Burgermeister Polymeric stent having modified molecular structures in selected regions of the hoops and method for increasing elongation at break
US20070256422A1 (en) * 2006-05-08 2007-11-08 Econo-Power International Corporation Production enhancements on integrated gasification combined cycle power plants
US20090317446A1 (en) * 2006-09-01 2009-12-24 Cornell Research Foundation, Inc. Calcium Phosphate Nanofibers
US20080220054A1 (en) * 2006-10-13 2008-09-11 Shastri V Prasad Modulation of drug release rate from electrospun fibers
US20080112998A1 (en) * 2006-11-14 2008-05-15 Hongjun Wang Innovative bottom-up cell assembly approach to three-dimensional tissue formation using nano-or micro-fibers

Also Published As

Publication number Publication date
WO2008118943A1 (en) 2008-10-02
EP2129517A1 (en) 2009-12-09
CA2680586A1 (en) 2008-10-02
JP2010522620A (en) 2010-07-08
US20080292839A1 (en) 2008-11-27
CN101687384A (en) 2010-03-31
US7879093B2 (en) 2011-02-01
EP2129517A4 (en) 2012-11-21

Similar Documents

Publication Publication Date Title
US7879093B2 (en) Electrospun apatite/polymer nano-composite scaffolds
Okamoto et al. Synthetic biopolymer nanocomposites for tissue engineering scaffolds
US7323190B2 (en) Cell delivery system comprising a fibrous matrix and cells
JP3483887B2 (en) Biocompatible porous matrix of bioabsorbable materials
Song et al. Electrospun polyvinyl alcohol–collagen–hydroxyapatite nanofibers: a biomimetic extracellular matrix for osteoblastic cells
DE602005004977T2 (en) Production method of bioabsorbable porous reinforced tissue implants and their implants
JP5579904B2 (en) Nonwoven tissue support skeleton
EP1395303B1 (en) Implantable biodegradable devices for musculoskeletal repair or regeneration
US20050158362A1 (en) Polymeric, fiber matrix delivery systems for bioactive compounds
AU2002231017A1 (en) Implantable biodegradable devices for musculoskeletal repair or regeneration
JPWO2006028244A1 (en) Bioabsorbable porous material
Scott et al. Advances in bionanomaterials for bone tissue engineering
KR102364168B1 (en) Scaffolds for bone regeneration and method for producing the same
Kanmaz et al. Electrospun polylactic acid based nanofibers for biomedical applications
Nelson et al. Nanostructured composites for bone repair
KR20130038598A (en) Barrier membrane for guided bone regeneration and manufacturing method thereof
US20220168105A1 (en) Bioabsorbable textiles and methods for joint function restoration
Tavakoli-Darestani et al. Poly (lactide-co-glycolide) nanofibers coated with collagen and nano-hydroxyapatite for bone tissue engineering
Chae Bio-inspired calcium phosphate/biopolymer nanocomposite fibrous scaffolds for hard tissue regeneration
Okamoto Synthetic biopolymer/layered silicate nanocomposites for tissue engineering scaffolds
Patrick Fabrication and characterization of antibacterial Polycaprolactone and natural Hydroxyapatite nanofibers for bone tissue scaffolds
Behera Fabrication of silk-based composite scaffold for bone-ligament-bone graft using aqueous polymeric dispersion technique
Xu Recent patents on nanostructured scaffolds for bone tissue repair and regeneration
Behera Fabrication and Characterization of a Polymer Based Three Compartmental Scaffold for Fibrocartilage Regeneration
Okamoto Ceramic nanocomposites: 17. Synthetic biopolymer/layered silicate nanocomposites for tissue engineering scaffolds

Legal Events

Date Code Title Description
AS Assignment

Owner name: UNIVERSITY OF CONNECTICUT, CONNECTICUT

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WEI, MEI;PENG, FEI;XU, ZHI-KANG;SIGNING DATES FROM 20090504 TO 20090518;REEL/FRAME:025516/0815

AS Assignment

Owner name: NATIONAL SCIENCE FOUNDATION, VIRGINIA

Free format text: CONFIRMATORY LICENSE;ASSIGNOR:UNIVERSITY OF CONNECTICUT HEALTH CENTER;REEL/FRAME:027440/0478

Effective date: 20111028

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: NATIONAL SCIENCE FOUNDATION, VIRGINIA

Free format text: CONFIRMATORY LICENSE;ASSIGNOR:UNIVERSITY OF CONNECTICUT;REEL/FRAME:040366/0596

Effective date: 20161013