Title of Invention: Porous orbital implant structure
Abstract: A porous structure for implantation into the orbital cavity of a mammal who has had an ocular enucleation, evisceration or who needs to have an orbital implant replaced, the structure comprising pores having a mean size of less than 200 micrometers. Also disclosed is a surgical method for placing an implant into a mammal who has had an ocular enucleation, evisceration or who needs implant replacement, whereby the implant obtains rapid ingrowth of connective and vascular tissues. The method comprises: selecting a porous ocular implant comprising pores with a mean size of less than 200 micrometers; and, placing the implant into an orbital cavity of a mammal.
Detailed Description: Part PAC: MODES FOR CARRYING OUT INVENTION
Part PAR: As disclosed herein, fibrovascular ingrowth into various porous ocular implants was investigated in an animal model, as a function of implant material composition, porosity, addition of growth factors, and use of coatings. Eighty-one new Zealand white rabbits underwent unilateral enucleation and implantation with ocular implants composed of the following materials:
Part PA1: coralline hydroxyapatite (HA) ("HA200") (Interpore 200, Interpore International, Irvine, Calif.); PA1 coralline hydroxyapatite ("HA500") (Interpore 500, Interpore International, Irvine, Calif.); PA1 synthetic HA ("synHA"); and, PA1 high-density porous polyethylene ("PP").
Part PAR_2: The HA200, HA500, and PP implants were implanted untreated or after treatment with recombinant human basic fibroblastic growth factor (Rh-.beta.FGF). Nine HA500 implants were implanted after coating with calcium sulfate (Plaster of Paris) to provide a smooth outer surface. Implants were harvested at 1-, 2-, 4-, or 8-week intervals and were examined histologically.
Part PAR_3: As discussed below, no significant differences in the degree of fibrovascular ingrowth were found as a function of implant composition. Surprisingly, significant increases in ingrowth were found in HA200 compared with HA500 implants. Increases in ingrowth were also found in Rh-.beta.FGF-treated implants compared with untreated controls. The calcium sulfate coated implants showed less vascularization compared with the uncoated implants, although the difference was not significant.
Part PAL: Composition
Part PAR_4: The two most popular materials used to manufacture porous implants, i.e., implants of PP and implants of coralline HA, were tested in the studies disclosed herein. Also, tested was synthetic hydroxyapatite. No significant differences in ingrowth were noted between implants composed of these materials (FIGS. 3 and 4), although they represent markedly different technologies.
Part PAL_2: Porosity
Part PAR_5: Porous implant materials, such as HA and PP, possess many of the characteristics presently deemed preferred for an ocular implant, and they offer clear advantages over solid, nonporous spheres. These preferred porous compositions allow fibrovascular tissue to grow into the implants; the presence of fibrovascular ingrowth is believed to prevent migration within the orbit and may help to minimize the chance of infection and exposure through breakdown of the thin overlying tissues of the conjunctiva and Tenon's capsule (Buettner, H. and Bartley, G., "Tissue Breakdown and Exposure Associated with Orbital Hydroxyapatite Implants" Am J Ophthalmol (1992) 113:669-673). A further advantage of porous implants is their ability to be directly integrated with the extraocular muscles, thereby maximizing the transfer of all latent muscle movement to the implant.
Part PAR_6: The importance of pore size in determining the nature of fibrovascular tissue was investigated in the present study. It was a surprising finding that the HA200 showed significantly better ingrowth than HA500. This result is believed to be due to the fact that smaller pores, in this case pores reported as 200-.mu.m, rather than pores reported as 500-.mu.m, may encourage fibrovascular ingrowth. This is a clinically important finding, for an additional reason: HA200 implants have a smoother surface and may thus be less prone to abrade the overlying tissues and are less likely to lead to exposures. It may also be easier to place these implants more deeply within the orbit.
Part PAL_3: Growth Factors
Part PAR_7: Growth factors have been successful in associated medical fields, and relatively recently have been used in ophthalmology. Thus, the present studies were performed to determine the applicability of growth factors in ocular implant surgery. Traditional methods of extracting growth factors from human placenta or bovine brain were laborious and ineffective (Rieck, P., et al., "Human Recombinant .beta.FGF Stimulates Endothelial Wound Healing in Rabbits." Current Eye Research (1992) 11:1161-1172); but recent progress in recombinant DNA technology has made it possible to produce growth factors on a scale large enough to make their therapeutic use a practical consideration.
Part PAR_8: Basic fibroblast growth factor (FGF) is stored within basement membranes and may exhibit angiogenic activity. Recombinant human basic fibroblast growth factor is derived from E. coli through recombinant DNA techniques. Rh-.beta.FGF is a 146 amino acid polypeptide from a family of growth factors that show a high affinity for heparin and have been extracted from a number of tissues such as eye, retina, brain, pituitary, and human placenta (Folkman, J., and Klagsbrun, M., "Angiogenic Factors" Science (1987) 235:442-447; Rieck, P., et al., "Recombinant Human Basic Fibroblast Growth Factor (Rh-.beta.FGF) in Three Different Wound Models in Rabbits: Corneal Wound Healing Effect and Pharmacology" Exp Eye Res (1992) 54:987-998). It is one of several angiogenic factors which in recent years have been fully purified, their amino acid sequences determined, and their genes cloned.
Part PAR_9: Recombinant human fibroblast growth factor beta (Rh-.beta.FGF) has been used in rabbit corneal studies to promote epithelial and endothelial wound healing (Rieck, P., et al., "Human Recombinant .beta.FGF Stimulates Endothelial Wound Healing in Rabbits." Current Eye Research (1992) 11:1161-1172).
Part PAR_10: Rh-.beta.FGF was used in the present study because of the demonstrated ability of this and related growth factors to induce new capillary blood vessel ingrowth in vitro and in vivo (Montesano, R., et al., "Basic Fibroblast Growth Factor Induces Angiogenesis In Vitro" Proc Natl Acad Sci USA (1986) 83:7297-7301; Baird, A., and Bohlen, P., "Fibroblast Growth Factors", In: Sporin, M. B., and Roberts, A. B., eds. Peptide Growth Factors and Their Receptors 1. (New York, Springer-Verlag, 1991). Capillary blood vessel formation is a complex process which includes endothelial cell proliferation, the sprouting of new capillaries, the migration of endothelial cells, and the breakdown of extracellular matrix surrounding existing capillaries.
Part PAR_11: Exogenously applied Rh-.beta.FGF may stimulate all of the biological activities required to elicit neovascularization (Rieck, P., et al., "Human Recombinant .beta.FGF Stimulates Endothelial Wound Healing in Rabbits." Current Eye Research (1992) 11:1161-1172).
Part PAR_12: The present studies investigated whether Rh-.beta.FGF could be affixed to PP and HA implants and, if so, whether they would enhance the rate of vascularization.
Part PAR_13: In the present studies, all implants treated with Rh-.beta.FGF showed significant increases in fibrovascular ingrowth compared with identical, untreated implants (FIG. 5). This finding is clinically significant, in view of the objective to decrease the latency of peg-fitting following enucleation, evisceration, or secondary implantation. It is also noteworthy that none of the implants treated with Rh-.beta.FGF in the present studies were observed to be exposed at any time, despite marked postoperative inflammation in orbits containing these implants.
Part PAR_14: Although previous corneal studies showed that Rh-.beta.FGF is tolerated in rabbits, a greater-than-normal inflammatory response was observed during the first 72 hours, characterized by increased erythema and orbital/peri-orbital edema. However, there were no episodes of extrusion or infection, and by 72 hours the rabbits showed no unusual symptoms. As appreciated by one of ordinary skill in the art, this finding suggests that the Rh-.beta.FGF did bind to some degree to the implants and that a lower dose might be used in any future situations.
Part PAR_15: As appreciated by those of ordinary skill in the art, concerns regarding the safety of growth factors, such as systemic absorption, must be taken into account when used as a means to enhance fibrovascular ingrowth into these implants. At least one previous study showed no evidence of systemic absorption when Rh-.beta.FGF was applied to the rabbit cornea to investigate its role in healing corneal epithelium (Rieck, P., et al., "Recombinant Human Basic Fibroblast Growth Factor (Rh-.beta.FGF) in Three Different Wound Models in Rabbits: Corneal Wound Healing Effect and Pharmacology" Exp Eye Res (1992) 54:987-998); although its behavior when placed within orbital tissues may be different.
Part PAL_4: Calcium sulfate coating
Part PAR_16: Donor sclera and other coverings are used by surgeons to provide for several therapeutic advantages, such as to: facilitate attachment of extra-ocular muscles to HA implants, to allow placement of the implant deeply within the orbit, and to prevent tissue breakdown over the rough anterior surface of HA implants. Biocompatible coatings that are used with orbital implants include polylactic acid, polyglycolic acid, and animal tissues such as sclera and fascia. Presently preferred coatings are disclosed in copending U.S. application Ser. No. 08/241,960 filed May 12, 1994 in the name of Arthur C. Perry. As disclosed herein, calcium sulfate was used to coat the HA spheres so as to provide some of the above-described therapeutic advantages of scleral wrappings.
Part PAR_17: An HA implant manufactured with a smooth covering that achieves these goals while not impeding vascularization would offer several benefits. For example, the cost of obtaining banked sclera would be saved and surgical time would be reduced, particularly relative to use of autologous sclera. Additionally, concerns of infectivity from donor tissue could be reduced, since some patients have refused to accept an HA implant coated with allogeneic sclera due to even a theoretical risk of virus transmission such as HIV (Dutton, J. J., "Coralline Hydroxyapatite as an Ocular Implant" Ophthalmology (1991) 98:370-7). Although a pre-coated HA implant may not replace the function of sclera or other tissue wrappings as a facile means of attaching the extraocular muscles, some surgeons already routinely attach the muscles directly to the HA, without the use of a scleral covering.
Part PAR_18: The implants disclosed herein were coated with a relatively thick layer of plaster of Paris, i.e., calcium sulfate of about 1 to 1.5 mm thickness. The calcium sulfate coating was still visible at the time of explantation in all cases (FIG. 6). While the material appeared to be well tolerated by the rabbit orbit, two of the calcium sulfate-coated HA implants were lost in the present studies and were presumed to have been exposed and extruded prior to harvesting. The orbital tissues in these rabbits were otherwise healthy in appearance.
Part PAR_19: Although the calcium sulfate-coated implants did not show significantly lower degrees of fibrovascular ingrowth, the loss of 2 specimens may have affected the statistical power of these results, as visual inspection showed some inhibition of ingrowth. Calcium sulfate coating may still be useful, although thinner layers of calcium sulfate may better achieve desired effects. Additionally, a more-controlled method of application of the coating may be desirable to minimize infections and to ensure the desired thickness can be achieved.
Part PAR_20: The present data regarding fibrovascular ingrowth is relevant due to its status as a prerequisite of complete integration of porous ocular implants, and because it may be necessary to achieve the complete cosmetic and psychological rehabilitation of an anophthalmic patient, since only a fully vascularized implant can accommodate a motility/support peg.
Part PAC_2: EXAMPLES
Part PAR_21: The present examples evaluated the rate and degree of fibrovascular ingrowth in common porous ocular implants as a function of material composition, porosity, treatment with growth factors, and the application of a calcium sulfate (Plaster of Paris) coating.
Part PAR_22: The present results indicated that smaller pore sizes, minimal physical barriers to ingrowth, and active growth induction by means of growth factors are means of achieving the speed and level of ingrowth needed to achieve the best surgical result and patient satisfaction with porous ocular implants. Particularly surprising was that smaller pore sizes led to enhanced fibrovascular ingrowth.
Part PAC_3: Example 1
Part PAL_5: Surgical Enucleation
Part PAR_23: The animals involved in the studies regarding the present invention were procured, maintained, and used in accordance with the Animal Welfare Act of 1966, as amended, and the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Academy of Sciences--National Research Council, as required by SECNAVINST 3900.38B.
Part PAR_24: Enucleation of the right eye was performed on 81 New Zealand white rabbits averaging 3 kg in weight. Intramuscular anesthesia was administered with 50 mg/kg of Ketamine and 5 mg/kg of Xylazine. The rabbits were also given an IM dose of 0.25 cc of penicillin G. The peri-orbital fur was shaved and the right eye and peri-orbital area were prepped with Betadine solution. A retrobulbar injection of Xylocaine 1% with epinephrine 1:100,000 was given and the surgical site was draped in a sterile fashion.
Part PAR_25: Following a complete peritomy, the extraocular muscles were tagged with double-armed 5-0 Vicryl suture and were then released from the globe. Muscles were isolated in the infer-nasal quadrant and the supero-lateral quadrant. Upon close inspection, the muscle complex in the supero-lateral quadrant appeared to be composed of two muscles, i.e., a rectus muscle with an attached oblique muscle. The globe was enucleated and pressure was applied to the posterior orbit for hemostasis.
Part PAC_4: Example 2
Part PAL_6: Calcium Sulfate Coating
Part PAR_26: To control the level of calcium sulfate infiltration into the pores, the coralline HA implants were filled with water and frozen prior to application of the calcium sulfate. All implants, except those treated with Rh-.beta.FGF, were sterilized by autoclaving prior to implantation. The Rh-.beta.FGF-treated implants were autoclaved prior to the application of the growth factor in a sterile solution.
Part PAC_5: Example 3
Part PAL_7: Surgical Implantation of the Various Implants
Part PAR_27: Twelve-millimeter ocular implants were prepared for implantation in all cases. A previous study found that 14-mm implants resulted in high rates of exposure (Rubin, P. A., et al., "Comparison of Fibrovascular Ingrowth into Hydroxyapatite and Porous Polyethylene Orbital Implants" Ophthalmic Plast Reconstr Surg (1994) 10:96-103), probably due to the small size of the rabbit orbit (J. K. Popham, personal communication, 1995).
Part PAR_28: All implants were immersed in a 20-mg/ml solution of gentamicin prior to implantation, except for those treated with fibroblast growth factor (Rh-.beta.FGF), which was in a sterile solution. Rh-.beta.FGF was obtained from the Department of Cell Biology, Scripps Research Institute, La Jolla, Calif. It was stored at -80.degree. C. and was passed over an endotoxin column to remove bacterial endotoxin before dilution to a concentration of 10 .mu.g/ml. The concentration was verified by a protein assay and spectrophotometry.
Part PAR_29: The implants were separated by type and placed in sterile 30-ml syringes, which were then filled with enough solution to completely immerse the implant. Each syringe was capped, the plunger was withdrawn to create a mild vacuum, and the barrel was agitated to release residual air from the implant. The implants were incubated lconway@example.org. C. Prior to implantation, the implants were gently rinsed twice with sterile PBS.
Part PAR_30: All implants were supplied by their respective manufacturers. The calcium sulfate and Rh-.beta.FGF treatments were applied as described herein.
Part PAR_31: Each 12-mm implant was placed in the center of the orbit between the muscles, and the muscles were sutured to each other over the anterior aspect of the implant. Since all implants were placed unwrapped (i.e., were not within a scleral shell), sterile plastic sleeves were created around the implants, fashioned from surgical drapes or gloves, to facilitate insertion of the implants deeply into the orbit. After the implant insertion, the sleeve material was removed, the conjunctiva was closed meticulously with 5-0 Vicryl suture, standard ophthalmic antibiotic ointment was applied to the orbit and, the lids were sutured together with at least one 5-0 Vicryl suture to allow instillation of ointment postoperatively. The rabbits were individually caged following recovery from anesthesia and each was observed closely during the first postoperative week. Antibiotic ophthalmic ointment was applied to the orbit daily during the first postoperative week.
Part PAC_6: Example 4
Part PAL_8: Surgical Explantation
Part PAR_32: For explantation, the rabbits were sacrificed at the predetermined intervals with intramuscular Ketamine and Xylazine, followed by 2.5 ml of intra-cardiac beuthanasia D. The implants and surrounding tissues were removed and fixed in Formalin. Each specimen was then soaked in water, dehydrated in alcohol, vacuum infiltrated, and then imbedded in methyl methacrylate.
Part PAC_7: Example 5
Part PAL_9: Specimen Analysis
Part PAR_33: The specimens were cut through the center into 1- to 2-mm sections using a wet diamond band saw. The slices were mounted on slides, recut using the sandwich method, and ground down to a thickness of approximately 200 .mu.m. All specimens were stained using the fibrin stain of Ladewig.
Part PAR_34: The sections were examined at a magnification of 50.times. using an overlying 1-mm grid. Each 1-mm increment of depth (level) from the edge of the implant was measured at 4 different quadrants by 2 investigators, for a total of 8 measurements per level, with the exception of the innermost level (the intersection of the axes) which was measured twice.
Part PAR_35: Two investigators independently characterized each section at 1-mm intervals (grids) along two perpendicular axes through the center of the implant (FIG. 1), and each investigator estimated the fibrovascular ingrowth in each grid according to the following scale: 0%, .ltoreq.25%, .ltoreq.50%, .ltoreq.75%, and .ltoreq.100% of available pore space. For example, a 1.times.1-mm grid containing some available pore area with no evidence of tissue ingrowth was graded 0%, while an area containing even one cell or tissue fiber was graded .ltoreq.25% (FIG. 2).
Part PAR_36: The inter-investigator assessments were consistent (correlation coefficient 0.935) throughout the investigation (p&lt;0.0001). The assessments for the eight data points in each level were averaged to derive the percent-ingrowth per level. The percent-ingrowth for all levels within an implant were averaged to derive the percent-ingrowth per implant type (see Table 3). Statistical differences in the degree of fibrovascular ingrowth among the implant types was determined using a 3-way analysis of variance.
Part PAC_8: Example 6
Part PAL_10: Results Following Surgical Explanation
Part PAR_37: Table 1 shows the breakdown of implant types, treatments and number of implants evaluated.
Part TBL: TABLE 1 ______________________________________ Implant type and treatment NUMBER NUMBER IMPLANT TYPE NUMBER EXTRUDED EVALUATED ______________________________________ HA200 12 0 12 HA200 GF 9 0 9 HA500 12 1 11 HA500 GF 9 0 9 HA500 CS 9 2 7 PP 12 0 12 PP GF 9 0 9 SynHA 9 0 9 ______________________________________ Legend: HA200, reported 200 .mu.mporosity coralline hydroxyapatite; HA500, reported 500 .mu.mporosity coralline hydroxyapatite; PP, porous polyethylene; SynHA; synthetic porous hydroxyapatite; GF, growth factortreated; CS, calcium sulfatecoated.
Part PAR_38: Three of each of the implants treated with growth factor (HA200 GF, HA500 GF, PP GF) were explanted at intervals of 1, 2, and 4 weeks to assess fibrovascular ingrowth. The same implant types without growth factor (controls) were harvested at 1, 2, 4, and 8 weeks. The synHA implants and those coated with calcium sulfate were harvested at 2, 4, and 8 weeks (see Table 2). Three of the HA500 implants (2 HA500CS, 1 HA500) were not present at the time of harvesting and were presumed to have been extruded.
Part TBL_2: TABLE 2 ______________________________________ Schedule of Explanation and Numbers Explanted, by Implant Type and Treatment Implant Type Week 1 Week 2 Week 4 Week 8 ______________________________________ HA200 3 3 3 3 HA200 GF 3 3 3 0 HA500 3 2 3 3 HA500 GF 3 3 3 0 HA500 CS 0 3 2 2 PP 3 3 3 3 PP GF 3 3 3 0 SynHA 0 3 3 3 ______________________________________
Part PAR_39: Exposure and Extrusion--At the time of explanation, two calcium sulfate-coated HA500 implants and one uncoated HA500 implant were absent and were presumed to have completely extruded from the orbit after the first postoperative week.
Part PAR_40: Of the implants present during explantation, 8 of 79 (10.1%) showed evidence of exposure. Exposure was only noted in the HA implants, as follows: 3 HA500, 3 calcium sulfate-coated HA500, and 2 HA200.
Part PAR_41: Inflammation and Infection--Most of the 81 rabbits demonstrated some thick, white conjunctival discharge from the orbit in the early postoperative period, which cleared spontaneously. In one rabbit, the discharge continued beyond this period but was responsive to additional applications of ointment. None of the rabbits showed signs of chronic orbital infection.
Part PAR_42: Most (56%) of the orbits containing implants treated with growth factor showed elevated levels of edema and erythema of the lids and peri-orbital tissues during the first 72 hours postoperatively. The level of inflammation was characterized as follows: 9 moderate (PP, 5; HA500, 4) and 6 severe (PP, 2; HA500, 4). None of the HA200 growth factor-treated implants were associated with elevated levels of inflammation. By postoperative day 3, all of the growth factor rabbits showed normal levels of inflammation and none showed signs of infection.
Part PAR_43: Notably, a significant difference (p=0.027) was found between the level of ingrowth in HA200 and HA500 implants, with the HA200 showing more complete ingrowth. This finding was surprising in view of disclosures regarding the impact of porosity on ingrowth. Previously, it had been reported that implants with larger pores would achieve better ingrowth relative to implants with smaller pores.
Part PAR_44: Implants treated with growth factor showed significantly greater (p=0.014) fibrovascular ingrowth than untreated implants.
Part PAR_45: Implants coated with calcium sulfate showed less ingrowth than uncoated implants, although the difference did not reach statistical significance (p=0.055).
Part PAR_46: There was a significant difference (p=0.001) in ingrowth between the 4 time periods (1 wk, 2 wks, 4 wks, 8 wks) in which the implants were explanted. In all cases, except in the case of PP during week 2, and in 3 instances of extruded implants which restricted the number of data points in a particular cell to 2 implants (see Table 3), more ingrowth was noted with each successive week.
Part TBL_3: TABLE 3 ______________________________________ Percent-ingrowth per implant as a function of material composition, porosity, growth factors, and coatings. Implant Type Week 1 Week 2 Week 4 Week 8 ______________________________________ HA200 60.6 64.9 78.5 91.3 HA200 GF (260)857-3162 NA HA500 54.7 35.2 [n = 2] 66.0 82.8 HA500 GF 61.6 81.8 79.3 NA HA500 CS NA 35.8 62.8 [n = 2] 41.9 [n = 2] PP 73.8 58.3 82.9 90.5 PP GF 76.0 81.1 85.4 NA SynHA NA 53.8 64.3 86.6 ______________________________________
Part PAC_9: Example 7
Part PAL_11: Pore Size Calculations
Part PAR_47: Previously, it has been reported that the HA 200 implants had pores sized at 200 micrometers, and that the HA 500 implants had pores sized at 500 micrometers. To confirm these pore sizes, and to determine the pore sizes of the synthetic HA (SynHA) and the porous polyethylene (PP), the following protocol was undertaken. Samples of materials were photographed in a scanning electron microscope (SEM) (Leica STEREOSCAN 400.RTM., Leica, Inc., Deerfield, Ill.). Coralline hydroxyapatite (e.g., HA200 and HA500) has an anisotropic structure. Because of this anisotropy, these samples were prepared for analysis by grinding both parallel and transverse to the long axis of the pore structure. Synthetic HA has a generally isotropic structure. Porous polyethylene is known to have a radial pore structure gradient (see, e.g., Klawitter, J. J. An Evaluation Bone Growth into Porous High Density Polyethylene J. Biomed. Mater Res. 10:311-323 (1976)) Accordingly, only the exterior surfaces of the porous polyethylene samples were evaluated.
Part PAR_48: Photographs of all samples were enlarged a defined amount, and cross-sections of pores were measured manually. The calibration scale printed on the photograph by the SEM was used to convert the measurements to pore dimensions. The longest dimension and the shortest dimension of each pore in the plane of the surface were determined. The two measurements were averaged to obtain a measurement of each pore. The mean of all measured pore sizes was calculated, and a histogram of pore size distribution was prepared for each implant-type measured.
Part PAR_49: FIG. 7 depicts a histogram of pore size measurements for transverse sections of the HA 200 samples. Forty samples were measured in this plane. The mean pore size was 64 micrometers.
Part PAR_50: FIG. 8 depicts a histogram of the pore size measurements from longitudinal sections of the HA 200 implants. Forty-three specimens were examined in this plane. The mean pore size was 89 micrometers.
Part PAR_51: FIG. 9 depicts a histogram for the pore size measurements of HA 500 implants taken along transverse sections. Fifty-eight specimens were examined in this plane. The mean pore size for these measurements was 262 micrometers.
Part PAR_52: FIG. 10 depicts a histogram of pore size measurements taken from longitudinal sections of HA 500 implants. Fifty-four specimens were examined in this plane. The mean pore size from these specimens was 220 micrometers.
Part PAR_53: FIG. 11 depicts a histogram of pore size measurements for the implants of porous polyethylene. These pore size measurements were taken at the surface of the implants. Twenty-one specimens were examined. The mean pore size was 563 micrometers.
Part PAR_54: FIG. 12 depicts a histogram for the pore size measurements taken from synthetic hydroxyapatite implants. Fifty-two specimens were examined. The mean pore size for these samples was 220 micrometers.
Part PAR_55: It was a surprising finding that the pore size data for the coralline hydroxyapatite implant differed so significantly from what was reported to be the approximate pore size for these materials. Moreover, the newly determined pore size information taken together with the data for fibrovascular ingrowth for the various samples, manifested the particularly surprising finding that enhanced fibrovascular ingrowth took place for hydroxyapatite implants (HA 200) having a mean pore size of 64 micrometers in a transverse section and 89 micrometers in longitudinal section. Taking an average of the transverse and longitudinal pore size determinations for this material, it was found that enhanced fibrovascular ingrowth took place in a material having an average pore size of approximately 77 microns. Previously reported studies directed and encouraged selection of implant materials having substantially larger pore sizes than such samples.
Part PAR_56: Closing
Part PAR_57: It must be noted that as used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a formulation" includes mixtures of different formulations and reference to "the method of treatment" includes reference to equivalent steps and methods known to those skilled in the art, and so forth.
Part PAR_58: Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar to equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are now described. All publications or applications mentioned herein are fully incorporated by reference herein.


{'bibliographic_information': "{'Patent Number': '060631171', 'Series Code': '9', 'Application Number': '0106291', 'Application Type': '1', 'Art unit': '378', 'Application Filing Date': '19980122', 'Title of Invention': 'Porous orbital implant structure', 'Issue Date': '20000516', 'Number of Claims': '19', 'Exemplary Claim Number(s)': '1', 'Assistant Examiner': 'Robert; Eduardo C.', 'Primary Examiner': 'Mancene; Gene', 'Number of Drawing Sheets': '12', 'Number of figures': '12'}", 'source_file': './grant/2000/pftaps20000516_wk20.txt', 'source_data': 'USPTO-Grant'}