IFGL Bioceramics Limited

Welcome to IFGL Bio Ceramics Limited

:: Surgical Clinical Results ::

Methods Synthetic hydroxyapatite powders have been prepared with a novel wet chemical route. Two models of porous orbital implants with the characteristic designs for both evisceration and enucleation surgery have been developed, characterized and implanted to consecutive 25 human subjects, 17 of which underwent evisceration surgery while the others were enucleated. The post-operative performances of these implants were evaluated from the degree of volume replacement (Implant + Prosthesis), presence/absence of lagophthalmos and lower eye-lid laxity, status of socket and fornices. Magnetic resonance imaging technique was employed to assess the stability of the implants within the socket and progressive fibrovascularisation as a function of time. Finally, motility of the implants as well as the prostheses (horizontal movements by Lister Perimeter) and subjective cosmetic results (qualitatively) have also been reported.

Results During the 21/2 years of follow-up study, no significant post-operative complications were noticed. One case however, showed an anterior implant exposure of 3 – 4 mm, which was then managed with donor sclera patch graft while in another one conjunctival thinning, was found, which was subsequently corrected by re-suturing the conjunctival mollifications. 14 out of the operated 25 patients had a very good movement of the prostheses (> 200 horizontal movement) while the other 11 patients had a fair motility (10 – 200). The degree of volume replacement (with prosthesis) was found to be very good for 21 patients with fair results for the other 4. All the patients reported cosmetic satisfaction with the post-operative performance of the prostheses.

Conclusion Synthetic hydroxyapatite-based integrated orbital implants with this superior design gave very good post-operative results from the viewpoint of clinical and cosmetic efficacy.

Key words Synthetic hydroxyapatite orbital implants, enucleation and evisceration surgery, MRI

Enucleation / evisceration of non-seeing, disfigured or painful eye leaves the patient with an empty or anophthalmic socket, that causes a volume depreciation of 7.0 to 7.5 c.c. from a total orbital volume of 30 c.c. More than 100 years back, for cosmetic restoration of these disfigured eyes, Mules1 at first introduced hollow spherical glass to fill this lost volume, which was a buried and non-integrated type of implant. The common problems arise from anophthalmic sockets have been summarized by Tyeres and Collins2 in the clinical entity of “Post Enucleation Socket Syndrome” (PESS). However, the exact etiopathological features have been understood only after 1990 when Smit et. al.3 employed CT Scan to study the anophthalmic sockets. The initial case studies with glass based implants showed a very high extrusion rate mostly because of inadequate surgical techniques. The following years saw the use of almost anything and everything ranging from gold to asbestos, as intra-orbital implant. Most of them dropped out of circulation very soon due to high rejection /complication rate4.

At present, it is being conceived that an ideal intra-orbital implant should be very light in weight (< 2 gms), simple in design and need to be completely buried within the sclera to eliminate chances of infection. Further, they should be chemically inert without any possibilities of bio-degradation and need to be smaller than the patient’s eyeball in size10. In addition, it has been felt that to achieve the highest motility, the implants with direct coupling options with the prosthesis need to be located centrally within the muscle cone of the orbital socket, integrated with extra ocular muscles, and properly anchored to the orbital tissues11, 12. Introduction of HAp implants however, has improved the scenario significantly8. It has been reported that implants made out of this material are biocompatible, non-toxic, non-reactive and do not exhibit any significant foreign body inflammatory reaction8, 14. Further, its unique ability to invite fibrovascular in-growth indicates its superiority over other materials15. This produces a far better stability of the implant and allows secondary drilling and direct coupling with the prosthesis, which enhances the movement of the cosmetic shell. However, it is also believed that the rough surface of porous hydroxyapatite derived from coral may lead to chronic inflammation, resulting in breakdown of the sclera and conjunctiva14. Further, the surgical technique for insertion and fixation of these implants with the extra-ocular muscles calls for a wrapping material over it which are often taken from Donors’ sclera. These wrapping materials carry the risks of transmitting the slow virus infections like human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS). Another real disadvantage of the coral derived implants is its source-dependant non-reliable properties and exorbitant cost factor, which has restricted their more wide-spread usage particularly in the third world countries. Therefore, in recent times synthetic HAp based orbital implants are being considered all over the world as a better and effective alternative16.

In the present study, synthetic HAp based implants with modified designs have been prepared for better volume augmentation, which after thorough in-vitro and in-vivo characterization have been implanted directly to 25 different human subjects without using wrapping materials. The post-operative results have been discussed with special emphasis on clinical results, degree of vascularization and subjective cosmetic rehabilitation.

Method

Synthetic hydroxyapatite powder has been prepared with a novel wet precipitation route, the detail of which has been described elsewhere17, 18. The properties of the synthesized powder is outlined in Table

Properties of the synthetic HAp powder, fired at 12500 C, which was used for the development of the orbital implant prostheses

Phase	Only HAp phase	Sp. Surface area	7.50 m 2/g
% crystallinity	98.26	Chemical Analysis
Avg. particle size	0.47 μm	CaO	53.58
Avg. crystallite size	29.07 nm	P 2O 5	40.89
JCPDS-PDF	9-432	Fe 2O 3	< 0.04
Ca/P molar ratio	1.667	TiO 2	< 0.01
Ca/P wt. ratio	2.151	MgO	< 0.2
Crystal structure	Hexagonal	Na 2O	< 0.12
Cell parameters	a ~ 6.878 A 0; c ~ 9.422 A 0	K 2O	< 0.3
Theo. density	3.153 g/c.c.	CdO	< 0.02
Grade	Biomedical; ASTM F1185-88 19	PbO	< 0.10
		As	Trace

The basic model of the orbital implants was conical in shape, which had a spherical anterior segment. At the first stage the model for the evisceration surgery was optimized and thereafter the direct muscle integration variety for the enucleation was developed. In the enucleation models two pairs of anchoring holes were provided for suturing of the eye muscles. The prostheses were having a major axis of length 18 – 20 mm while the anterior parts were having a diameter of 16 – 18 mm


(a)	(b)
Actual prostheses (a) for the evisceration surgery and (b) for enucleation surgery.

These ocular implants along with the test samples prepared in the identical way, were characterized for different physical and mechanical properties. The final properties of the implants are outlined in

properties of ocular prostheses

Property	Value
Theoretical density	3.16 g / c. c.
Bulk density	0.61 g / c. c.
Total weight	2 g
Porosity	75 %
Pore size	30 – 250 µm
Compressive strength	1 – 2 MPa
Wear factor under 1000 g load and sliding speed of 30 m / min.	1.2 x 10 -10 cm 2 / g

Before going into the actual implantation in the human patients, the implants were studied in vivo in animal subjects to establish bio-compatibility and non-toxicity of the materials and also their functional superiority. A detailed experimentation with these implants on the canine subjects along with the successful outcomes has been published elsewhere18. Finally, these implants were tried in twenty-five consecutive patients who had undergone either enucleation or evisceration type destructive surgery from October, 2001 to February, 2004. The details of the patients, their complications, operated oculus sinister (OS)/oculus dexter (OD) etc. are outlined in

Clinical data including the details of the patients, their indications/complications and the type of surgery for insertion of synthetic HAp based elliptical orbital implant (major axis : 20 mm, minor axis :16 mm)

Sl. No. of patient	Patients Age/ Sex	Oculus sinister (OS)/ Oculus Dexter (OD)	Process of Surgery	Reasons for surgery
1	56/F	OS	Evisceration	Endophthalmitis
2	50/M	OD	Evisceration	Anterior staphyloma with pseudo-cornea
3	32/F	OD	Enucleation	Anophthalmic socket
4	30/F	OD	Evisceration	Secondary glaucoma with corneal opacity
5	26/M	OS	Evisceration	Secondary glaucoma with corneal opacity, facial palsy, left side
6	27/M	OD	Evisceration	Neovascular glaucoma with corneal opacity
7	18/F	OS	Evisceration	PVR with neovascular glaucoma
8	16/M	OS	Enucleation	Secondary glaucoma with PVR and failed PK
9	22/F	OS	Enucleation	Anterior staphyloma with adherent leucoma
10	26/F	OD	Evisceration	Congenital glaucoma (Buphthalmos), both eyes with corneal opacity
11	55/F	OD	Evisceration	Neovascular glaucoma
12	19/F	OS	Enucleation	Phthisical eye
13	67/M	OD	Evisceration	Post-operative endophthalmitis, (painful blind eye)
14	9/M	OS	Enucleation	Nanophthalmos with phthisical eye
15	33/M	OD	Evisceration	Post traumatic phthisical eye with corneal band degeneration
16	48/M	OS	Enucleation	Painful blind eye
17	36/F	OD	Enucleation	Phthisical eye with corneal band degeneration
18	14/F	OS	Evisceration	Painful blind eye with anterior staphyloma
19	65/F	OS	Evisceration	Painful blind eye
20	65/F	OS	Evisceration	Corneal perforation following ulcer
21	38/M	OS	Evisceration	Traumatic endophthalmitis
22	50/M	OD	Evisceration	Sloughes and corneal ulcer
23	20/M	OS	Evisceration	Painful blind eye
24	14/F	OS	Evisceration	Painful blind eye
25	42/M	OD	Enucleation	Painful blind eye

For the present case studies, human subjects were selected from the patients with blind / disfigured eye (with or without pains) suffering from intraocular tumors and/or trauma with injury confined tissue only. The patients suffering from complex orbital trauma, secondary metastases in orbit, panophthalmitis and other infectious diseases were not included in the study. Further, the patients with gross contracted socket who require secondary implantation and the ones suffering from systemic malignancy have also been excluded for the complications from the influence of these associated interfering factors. Both the eyes of all the human subjects were clinically examined prior to the operations. In addition, general health conditions of all the patients were clinically checked up and for the purpose, routine blood tests for sugar, hemoglobin and TC/DC, blood pressure, electrocardiogram and ultrasonic evaluations were conducted wherever necessary. Pre-operative photographs of the enucleated, eviscerated eyes of all the patients were taken to compare and assess the cosmetic gain after the surgery. Generally, prior to the operations, in all the cases, topical antibiotic drops were used.

The evisceration and enucleation techniques adapted in the present study to insert the hydroxyapatite implants are outlined in Fig. 3 (a) and (b). In both the surgery (enucleation/evisceration), peribulbar anesthesias were used.

(a)

(b)

Description of (a) enucleation and (b) evisceration surgery.

Post operative follow-up was conducted on each patient on the next day after the operation which continued on 1st, 3rd and 6th week and also on 3rd, 6th month, and one year thereafter. To eliminate any complications, along with frequent applications of antibiotic drops, intra-operative intravenous (IV) monocef injection (1 g) and oral cefadrox (500 mg) were used twice daily for 1 week while indomethacin (75 mg) was also employed once daily up to 3 weeks after the surgery. Conjunctival stitches were removed on the 7th day and subsequently, on the 3rd week after satisfactory inspection of the progressive healing of the surgical wound, patients were referred to the ocularist for fitting of the moulded prosthesis. Magnetic resonance imaging (MRI) of the implant was performed 4 and 6 months after surgery on a Signa (SYS # GEMSOW; General Electric, USA) of 1.5 T scanner. For the study after 4 months, Gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) contrast-was used to enhance T1-weighted fat-suppressed images, using head coil. During the imaging, the ratio of the repetition time (TR) to echo time (TE) was maintained at 660/15, while the number of image matrix was kept as 192 X 256, field of view (FOV) as 230 X 230 and the slice thickness as 3 mm each in the axial places. T2-weighted image (TR/TE = 4000/87) with the number of imaging matrix being 256 X 256, FOV of 16 X 16 and the slice thickness of 3 mm was employed to view the degree of vascularization of the HAp orbital implant after 6 months of surgery in the axial places either. The fibrovascular in-growth within the orbital implants was considered as a region of increased signal intensity in contrast-enhanced T1-weighted image. The degree of volume replacement (with implant and prosthesis) was measured quantitatively by exophthalmometer while; the qualitative assessment was performed by observing the upper eye-lid sulcus deformity. Motility of the prosthesis was measured by a Lister Perimeter. In case of symmetrical horizontal movements of 200, the degree of motility was assumed to be good, while the performances were taken as fair and poor for the movement of and < 100 respectively. Status of the socket and fornices along with the lower eye-lid laxity and the presence/absence of lagophthalmos were also studied in each patient.

Results

Altogether, thirteen female and twelve male patients, within the age group ranging between 9 to 67 years, were operated for insertion of synthetic HAp-based orbital implants. Seventeen out of twenty five patients underwent evisceration surgery while the other eight patients were enucleated. Postoperative clinical study pointed out that twenty-one patients had a very good volume replacement while for the other four, the results were fairly good. Implants were observed to be very stable for as many as 24 patients and only in one case an anterior implant exposure of 3 – 4 mm occurred, which however could be subsequently managed by patch grafting with donor sclera (Fig. 4). All the patients were satisfied with the subjective cosmetic results after the surgery. Fig. 5 shows the degree of volume replacement (implant and prosthesis) quantitatively for all the 25 patients, as measured in the exophthalmometer. The fig. also compares the replaced volume with that of the natural eyes which are very close in most of the cases.

Summarizes the results of the postoperative clinical studies after the respective enucleation/evisceration surgery. The qualitative measurement of the degree of volume replacement, motility of both the implant and the prosthesis post-operatively and subjective cosmetic rehabilitation are also shown by pie chart in the

Degree of volume replacement			Motility of the implant	Motility of the prosthesis*	Lagophthalmos	Status of socket and fornices	Lower eye-lid laxity	Subjective cosmetic results
Quantitative		Qualitative (upper eye-lid sulcus deformity)
Natural eye	Operated eye	Qualitative (upper eye-lid sulcus deformity)
17	17.5	Mild	Good	Good	Absent	Adequate	Absent	Fair
18	17	Mild	Fair	Fair	Absent	Good	Absent	Fair
20	21	Absent	Good	Good	Absent	Healthy and adequate	Absent	Fair
16.5	17	Mild	Good	Fair	Absent	Adequate	Absent	Good
19	18.5	Mild	Fair	Fair	Present**	Good	Present	Fair
18	18.5	Mild	Fair	Fair	Absent	Shallow lower fornix†	Absent	Fair
20	19.5	Mild	Fair	Fair	Absent	Good	Absent	Good
18	18	Absent	Good	Good	Absent	Healthy socket with adequate fornices	Absent	Good
17.5	18.5	Absent	Good	Good	Absent	Healthy	Absent	Good
23	22.5	Mild	Fair	Fair	Absent	Good	Absent	Fair
19	18.5	Mild	Good	Fair	Absent	Good	Absent	Fair
18	17.5	Mild	Good	Good	Absent	Good	Absent	Good
22	21	Mild	Good	Fair	Absent	Healthy	Absent	Fair
22	21	Absent	Good	Good	Absent	Healthy	Absent	Good
20	20	Absent	Good	Good	Absent	Healthy	Absent	Good
23	20	Mild	Fair	Fair	Absent	Healthy	Absent	Fair
22	21	Absent	Good	Fair	Absent	Healthy	Absent	Good
Disfigured	21	Absent	Good	Fair	Absent	Healthy	Absent	Good
23	21	Mild	Good	Good	Absent	Healthy	Absent	Good
21	20	Mild	Fair	Fair	Absent	Healthy	Absent	Fair
18	18	Absent	Good	Fair	Absent	Healthy socket; fornices – well formed‡	Absent	Good
19	19	Absent	Good	Good	Absent	Healthy#	Absent	Good
18	18	Absent	Good	Fair	Absent	Healthy##	Absent	Good
19	19.5	Absent	Good	Fair	Absent	Healthy¢	Absent	Good
19	19	Mild	Good	Fair	Absent	Healthy; well formed¢¢	Absent	Fair

* Horizontal movements; 200 Good; 100 <200 Fair; <100 Poor.

** Further surgery was performed for correction of lagophthalmos.

†Exposures of HAp implant anteriorly (about 3 - 4 mm), which was subsequently corrected by scleral patch graft to cover implant exposure.

‡Immediate post-operative oedema was found along with a severe Chemasin, but there were no requirement of further surgery.

# Severe post-operative inflammation without requirement of further surgery.

## More inflammation encountered, but again, not requiring any further surgery.

¢ Found severe inflammation in the early post-operation, but, no requirement of further surgery.

¢¢After surgery, conjunctival thinning was found, which was subsequently corrected by re-suturing the conjunctival mollifications.

Anterior implant exposure of 3 - 4 mm, which however could be subsequently managed by patch grafting with donor sclera

Graphical representation of the quantitative assessment of the degree of volume replacement (implant + prosthesis), measured by exophthalmometer. The variation from the natural to the operated eye is also mentioned.

(a)

(b)

(c)

(d)

Pie chart representing some of the post-op. outcome (a) qualitative determination (by upper eye-lid sulcus deformity) of the degree of volume replacement (implant + prosthesis), (b) motility of the implant, (c) motility of the prosthesis, determined by measuring the horizontal movement by Lister perimeter and (d) the subjective cosmetic results.

MRI with Gd-DTPA contrast-enhanced T1-weighted fat-suppressed images, using axial views, taken after 4 months of surgery showed diffuse and homogeneous enhancement for one patient (Fig. 7). Fibrovascular ingrowth showed enhancement and cases with contrast enhancement in the peripheral and posterior aspects were most in number, one such case is shown in Fig. 8. It may be mentioned that, T2-weighted image as well as T1-wieghted image was not useful for evaluating fibrovascular ingrowth of an implant as it showed inhomogeneous signal intensity. Still, we have found, from the T2-wieghted image, after 6 months, the fibrovascular ingrowth was complete

MRI with Gd-DTPA contrast-enhanced T1-weighted fat-suppressed image of synthetic HAp-based orbital implant 4 months post-operatively. Axial view shows diffuse and homogeneous enhancement.

MRI with Gd-DTPA contrast-enhanced T1-weighted fat-suppressed image of synthetic HAp-based orbital implant 4 months post-operatively. Axial view shows contrast enhancement in the peripheral and posterior aspects.

MRI with T2-weighted image of synthetic HAp-based orbital implant 6 months post-operatively

DiscussionOrbital implants are used to resolve cosmetic problems by replacing the volume of an orbit after enucleation or evisceration surgery, so that installation of an ocular prosthesis is possible. Synthetic hydroxyapatite-based intra-orbital implant developed by us, was actually served the purpose, it was less expensive than the conventional coral one and the cosmetic rehabilitation was found out to be completely satisfactory, as it took a less time for complete degree of vascularization and as an outcome the degree of motility of the implant as well as the prosthesis. 72% of the patients had very good implant motility {Fig. 6 (b)}, while, only 36% had very good prosthesis motility {Fig. 6 (c)}, 64% patients had a fair motility of the prosthesis. Improvement in movement of implant-prosthesis using these implants requires insertion of a motility peg into an implant, and the motility of an orbital implant is transmitted to an ocular prosthesis by way of a ball-and-socket type of peg-prosthesis connection. The study of peg-prosthesis connection by motility/support peg is under trial and that is why we have not discussed that point in detail. It has been found that, the total movement found after application of the prosthesis was very encouraging. In the qualitative point, 56% of the cases had absolute absence of any post-operative upper eye-lid sulcus deformity {Fig. 6 (a)}, clearly indicating the volume augmentation physically. While, only 44% had a mild post-operative upper eye-lid sulcus deformity. We didn't find any case for moderate and/or severe deformity, in this regard. The quantitative measurement of this volume augmentation of these implants, due to tissue in-growth, showed less than 5% variation from the natural eye (Fig. 5), which could be studied by the growth-rate study of Mülliermei. All of the patients showed healthy socket and adequate fornices, evidenced by the photograph of one of the patients in Fig. 11. But, in order to evaluate successful connection of an orbital implant with normal orbital structures by fibrovascular ingrowth and to determine the proper time for successful connection with an ocular prosthesis, noninvasive test methods like MRI is very much proven fact, as it provides more accurate information. The contrast enhanced MRI (by Gd-DTPA) is very much useful to study the slow blood flow and increased blood vessels20, 21. High signal intensity after intravenous infusion of Gd-DTPA implies fibrovascular ingrowth. In this study, the regions of contrast enhancement were found to extend toward a centre by fibrovascular ingrowth with time. This ingrowth takes place through the scleral window and the surface open pores of the implant centripetally from the surrounding to the centre homogeneously. The tissue ingrowth was complete by 6 months after surgery. This finding is important because of the fact that recognition of an extent of fibrovascular ingrowth into an orbital implant by such mechanism is essential for determining the time to drill for motility of an ocular prosthesis. In case of only one patient, we have found the presence of lagophthalmos as well as lower eye-lid laxity; it was, though, corrected subsequently by an additional surgery. Apart from this, 4 patients had minor post-surgical problem, but, in all the cases, there were no requirement of the subsequent surgery. The problem faced by other 2 patients, had minor second surgery. But, overall cosmetic results were superior from the conventional one used for this purpose. 56% of the patients felt a very good cosmetic outcome while 44% thought their cosmetic rehabilitation being fair {Fig. 6 (d)}. This may be inferred from the results of the horizontal movement recording (by Lister perimeter) of the prostheses. We have found 36% of the patients had a horizontal movement greater than 200, 64% of them had more than 100 but less than 200 horizontal movement. This means, these prostheses having a very unique shape and surface roughness gives a better horizontal movement than previously reported22, 23. Fig. 12 shows the total movement of the implant + prosthesis with the application of motility peg of one of the patient. So, it may be concluded that, synthetic hydroxyapatite-based integrated orbital implant with this unique design invites fibrovascular ingrowth faster than the conventional spherical one made from coral. For its very smooth surface and very lightweight, the socket remains very healthy even after a long period of post-operative study and subsequently it gives a better implant and prosthesis motility. Still, we recommend a motility/support peg would be even more effective to get even better motility and MRI with Gd-DTPA enhancer is a useful technique for assessing the time to attach the peg.

Status of the socket and fornices post-operatively taken after 3 weeks after surgery

References :

1. Mules PH. Evisceration of the globe, with artificial vitreous. Opthalmol Soc UK 1885; 5:200-206.

2. Tyers AG, Collins JR. Orbital implants and post-enucleation socket syndrome. Trans Ophthalmol Soc UK 1982; 102: 90-92.

3. Smit TJ, Koornneef L, Zonneveld FW. Brit J Ophthalmol 1991; 75: 342-343.

4. Perry AC. Integrated orbital implants. Adv Ophthalmic Plast Reconstr Surg 1988; 8: 75-81.

5. Ruedemann AD. Plastic eye implant. Am J Ophthalmol 1946; 29: 947-952.

6. Cutler NL. A positive contact ball and ring implant for use after enucleation. Arch Ophthal 1947; 37:73-81.

7. Gougelmann HP. The evolution of the ocular motility implant. In: Shannon GM, Connelly FJ (eds). Oculoplastic surgery and prosthetics. international ophthalmology clinics. Little Brown: Boston; 1970. pp 689-711.

8. Dutton JJ. Coralline hydroxyapatite as an ocular implant. Ophthalmology 1991; 98: 370-377.

9. Ashworth JL, Rhatigan M, Sampath R, Brammar R, Sunderland S, Leatherbarrow B. The hydroxyapatite orbital implant: a prospective study. Eye 1996; 10: 29-37.

10. Levine MR. Extruding orbital implant: prevention and treatment. Ann Ophthalmol 1980; 12: 1384-1386.

11. Goldberg RA, Holds JB, Ebrahimpour J. Exposed hydroxyapatite orbital implants. Report of six cases. Ophthalmology 1992; 99: 831-836.

12. Kim YD, Goldberg RA, Shorr N, Steinsapir KD. Management of exposed hydroxyapatite orbital implants. Ophthalmology 1994; 101: 1709-1715.

13. Hench LL. Bioceramics: from concept to clinic. J Am Ceram Soc 1991; 74: 1487-1510.

14. Nunery WR, Heinz GW, Bonnin JM et al. Exposure rate of hydroxyapatite spheres in the anophthalmic socket: histopathologic correlation and comparison with silicone sphere implants. Ophthal Plast Reconstr Surg 1993; 9: 96-104.

15. Holmes RE. Bone regeneration within a coralline hydroxyapatite implant. Plast Reconstr Surg 1979; 63: 626-633.

16. Rivera-Munoz E, Diaz JR, Rogelio Rodriguez J, Brostow W, Castano VM. Hydroxyapatite spheres with controlled porosity for eye ball prosthesis: processing and characterization. J Mater Sci: Mater Med 2001; 12: 305-311.

17. Sinha MK, Basu D, Sen PS. Porous hydroxyapatite ceramic and its clinical applications. Interceram 2000; 2: 102-105.

18. Kundu B, Sinha MK, Mitra MK, Basu D. Fabrication and characterization of porous hydroxyapatite ocular implant followed by an in vivo study in dogs. Bull Mater Sci 2004; 27: 133-140.

19. ASTM F1185-88 (Reapproved 1993). Standard specification for composition of ceramic hydroxylapatite for surgical implants, Annual Book of ASTM Standards, March 1993, pp 473-474.

20. Healy ME, Hesselink JR, Press GA, Middleton MS. Increased detection of intracranial metastasis with intravenous Gd-DTPA. Radiology 1987; 165: 619-624.

21. Zimmermann CF, Schatz NJ, Glaser JS. Magnetic resonance imaging of optic nerve meningiomass: enhancement with gadolinium-DTPA. Ophthalmology 1990; 97: 585-591.

22. Colen TP, Paridaens DA, Lemij HG, et al. Comparison of artificial eye amplitudes with acrylic and hydroxyapatite spherical enucleation implants. Ophthalmology 2000; 107: 1889-1894

23. Custer PL, Trinkaus KM, Fornoff J. Comparative motility of hydroxyapatite and alloplastic enucleation implants. Ophthalmology 1999; 106: 513-516.