Journal of Refractive Surgery

Original Article 

Study of the Force Dynamics at the Capsular Interface Related to Ciliary Body Stimulation in a Primate Model

Jorge L. Alió, MD, PhD; Joshua Ben-Nun, MD

Abstract

PURPOSE:

To study the mechanical dynamics between the zonuli-capsular complex and an accommodating intraocular lens mechanics simulator using pharmacological stimulation of the ciliary body in a primate eye.

METHODS:

Following phacoemulsification removal of the lens, force/movement gauges simulating the accommodating intraocular lens mechanics were implanted in 8 primate eyes (4 positioned in-the-bag and 4 on-the-bag). The gauge readings were taken under full effect of pilocarpine 4% or atropine 1% starting 6 weeks after surgery and following 3-month intervals for 30 months.

RESULTS:

An average movement of 390 µm for on-the-bag gauges and 145 µm for in-the-bag gauges was documented at 3 months postoperatively. The mechanical compliance of in-the-bag gauges rapidly deteriorated with capsular fibrosis developing inside the gauge and the capsular bag shrinking around it. On-the-bag gauges remained functional but the initial compliance was compromised over time by the pressure build up caused by the fibrotic capsular bag.

CONCLUSIONS:

Following phacoemulsification, capsular fibrosis causes disappearance of the mechanical forces detected by an in-the-bag gauge. An on-the-bag gauge detects active forces at the sulcus lasting at least 5 years, although the contracting capsule pressure compromises its compliance. These findings have important implications for future accommodating intraocular lens designs.

[J Refract Surg. 2015;31(2):124–128.]

From the Vissum Corporation, Alicante, Spain; and Division of Ophthalmology, Universidad Miguel Hernández, Alicante, Spain.

This study has been financed in part by NuLens, Ltd., Hertzliya, Israel. Supported in part by a grant from the Spanish Ministry of Science and Innovation, Centro para el Desarrollo Tecnologico Industrial (CDTI), CENIT: “Customized Eye Care”, CeyeC (CEN-20091021).

Dr. Ben-Nun holds intellectual property on the NuLens accommodative intraocular lens. Dr. Alió has no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (JB-N); data collection (JB-N); analysis and interpretation of data (JLA); drafting of the manuscript (JLA, JB-N); critical revision of the manuscript (JLA); statistical expertise (JB-N); supervision (JLA)

Correspondence: Jorge L. Alió, MD, PhD, Avda de Denia s/n, Edificio Vissum, 03016 Alicante, Spain. E-mail: jlalio@vissum.com

Received: September 17, 2014
Accepted: December 22, 2014

Abstract

PURPOSE:

To study the mechanical dynamics between the zonuli-capsular complex and an accommodating intraocular lens mechanics simulator using pharmacological stimulation of the ciliary body in a primate eye.

METHODS:

Following phacoemulsification removal of the lens, force/movement gauges simulating the accommodating intraocular lens mechanics were implanted in 8 primate eyes (4 positioned in-the-bag and 4 on-the-bag). The gauge readings were taken under full effect of pilocarpine 4% or atropine 1% starting 6 weeks after surgery and following 3-month intervals for 30 months.

RESULTS:

An average movement of 390 µm for on-the-bag gauges and 145 µm for in-the-bag gauges was documented at 3 months postoperatively. The mechanical compliance of in-the-bag gauges rapidly deteriorated with capsular fibrosis developing inside the gauge and the capsular bag shrinking around it. On-the-bag gauges remained functional but the initial compliance was compromised over time by the pressure build up caused by the fibrotic capsular bag.

CONCLUSIONS:

Following phacoemulsification, capsular fibrosis causes disappearance of the mechanical forces detected by an in-the-bag gauge. An on-the-bag gauge detects active forces at the sulcus lasting at least 5 years, although the contracting capsule pressure compromises its compliance. These findings have important implications for future accommodating intraocular lens designs.

[J Refract Surg. 2015;31(2):124–128.]

From the Vissum Corporation, Alicante, Spain; and Division of Ophthalmology, Universidad Miguel Hernández, Alicante, Spain.

This study has been financed in part by NuLens, Ltd., Hertzliya, Israel. Supported in part by a grant from the Spanish Ministry of Science and Innovation, Centro para el Desarrollo Tecnologico Industrial (CDTI), CENIT: “Customized Eye Care”, CeyeC (CEN-20091021).

Dr. Ben-Nun holds intellectual property on the NuLens accommodative intraocular lens. Dr. Alió has no financial or proprietary interest in the materials presented herein.

AUTHOR CONTRIBUTIONS

Study concept and design (JB-N); data collection (JB-N); analysis and interpretation of data (JLA); drafting of the manuscript (JLA, JB-N); critical revision of the manuscript (JLA); statistical expertise (JB-N); supervision (JLA)

Correspondence: Jorge L. Alió, MD, PhD, Avda de Denia s/n, Edificio Vissum, 03016 Alicante, Spain. E-mail: jlalio@vissum.com

Received: September 17, 2014
Accepted: December 22, 2014

Natural accommodation is an optomechanical process where ciliary muscles are stimulated to induce a curvature change of the crystalline lens capsule via an action of the zonuli on the fibrotic capsular bag. It has been recognized for a long time1,2 that age-related changes of the crystalline lens morphology result in rapid deterioration of its optomechanical compliance in approximately the fourth to fifth decades of life; however, studies have shown that the aging ciliary muscle remains active throughout life.3,4 The force that the ciliary muscle applies on the crystalline lens has also been studied and found to be approximately 1.5 gram force (0.015 N)5,6 with more recent studies7,8 using computerized modelling and analysis (finite element analysis) estimating this force to be approximately 6.5 gram force (0.065 N). The ciliary muscle stroke distance that applies this force on the crystalline lens has also been studied and is calculated to be at 320-µm range per ciliary body unit. These mechanical data are relevant for the development of accommodating intraocular lenses (IOLs). The core concept of the current IOL power-calculating formulas is that ocular optics have a linear “optical-bench” arrangement with lifelong stability. The evolution in the surgical technique and the advances in IOL technology have achieved impressive surgical outcomes in the form of a near perfect “presbyopic eye.” This outcome was considered to be the ultimate goal for cataract surgery until the quest for restoring accommodation began. The development of an optomechanical device activated by the ciliary muscles and capable of providing full or partial range accommodation is a challenge for current IOL technology.

The first step in this direction implies a conceptual shift from pure optical solutions in the form of static lenses arranged on the optical bench to optomechanical solutions provided by “lenses” that are actually optome-chanical devices, which, following lens surgery, are capable of transforming the mechanical forces generated at the zonular-capsular diaphragm into controlled optical power of sufficient range. The study of the postoperative mechanics of the interface between the zonuli-capsular complex and an IOL is a fundamental issue because these are the forces available for the optical function of an accommodating IOL. In this study, we investigated the force dynamics of the capsular bag following phacoemulsification surgery using a micromechanical gauge device interfacing the anterior or posterior capsule surface of primate eyes. The mechanical dynamics present when the device was placed at the ciliary sulcus or inside the capsular bag were studied over 30 months using pharmacological stimulation to induce cyclospasm or cycloplegia.

Materials and Methods

All animal experiments were submitted and approved by the Experimental Research Ethical Committee from Miguel Hernández University.

Experimental Animal Model

A micromechanical force device was implanted in 1 eye of 10 primates (Macaca fascicularis) aged 7 to 8 years and followed up for 30 months. Five gauges were placed inside the capsular bag and 5 gauges were placed at the ciliary sulcus. All surgeries were performed by one surgeon (JLA) in the laboratory of Miguel Hernández University, Alicante, Spain.

Prior to the surgery, the animal received an intramuscular injection of Baytril (Bayer AG, Leverkusen, Germany) 0.4 mL with a concentration of 100 mL/2.5 g of meloxicam and atropine.

Ketamine was then used for induction of general anesthesia by the intramuscular route, in combination with diazepam. Following intubation, an endotracheal tube was secured. A non-rebreathing circuit was used with isoflurane as inhalational anesthetic. For postoperative analgesia, Bufrenorphine (SUBOXONE; Reckitt Benckiser Pharmaceuticals, Inc., Richmond, VA) (opioid analgesic) was given by the intramuscular route, as needed, for 24 or 48 hours. Follow-up procedures were performed under good sedation-analgesia conditions, using an intramuscular injection of ketamine in combination with medetonine (alpha-agonist sedative).

Surgical Protocol

All surgical procedures were performed by the same surgeon (JLA). The pupil of the operated eye was widely dilated with tropicamide and phenylephrine. Surgical field preparation was the same as used for human eye surgery. After anesthetizing the animal, adequate pupil mydriasis was accomplished with an intracameral injection of a preservative-free mixture of 0.1 cyclopentolate and 10% phenylephrine. Two calibrated 1-mm corneal incisions were performed at two limbal locations and viscoelastic material was injected into the anterior chamber via one of them. A small 4-mm central capsulorhexis was then performed with coaxial capsular forceps. Bimanual 1-mm phacoemulsification was used to eliminate the lens followed by bimanual irrigation/aspiration of the cortex and the anterior capsular epithelial cells. One of the corneal incisions was increased to 8.0 mm, enabling the insertion of a micromechanical gauge under cohesive viscoelastic into the anterior chamber. The haptics of the device were positioned at the anterior chamber angle while the gauge itself passed through the pupil to interface with the anterior capsule being implanted in the sulcus (4 eyes) or the posterior capsule via the capsulorhexis being implanted intracapsular (4 eyes). A surgical peripheral iridectomy at the 12-o’clock position was performed and all viscoelastic material was washed out by bimanual irrigation/aspiration. The main incision was sutured with 10-0 nylon monofilament sutures. At the end of each procedure, an intracameral injection of 0.1 cc of 1% cefuroxime and 0.2 cc of triamcinolone suspension was performed for prevention of postoperative infection or inflammation. Only one eye of each animal was used for the study.

The pressure readings following the surgical implantation were taken in a noncontact mode using an external reading device.

Postoperative Care

A mild general anesthesia with spontaneous breathing and no intubation was used for follow-up.

A follow-up examination was done at 24 and 72 hours postoperatively. With no remarkable events, the subsequent follow-up was twice a week up to 1 month. During the second month, the follow-up was performed once a week. From the third to sixth month, the follow-up was every 2 weeks. From the sixth to twelfth month the follow-up was once a month. Following this period, examinations were performed every 6 months.

Postoperative Treatment. Topical administration (once a day) of ofloxacin, 0.1% dexamethasone, and 1% atropine was used in all cases at each examination. A periocular injection of 1 cc of a depot form of triamcinolone acetonide was performed at the first postoperative observation and during the first and second months postoperatively. When significant intraocular inflammation was detected, systemic corticosteroid treatment (prednisone from 1 to 2 mg/kg weight) was used for 1 week or until significant resolution was observed. When the early development of a fibrin membrane was detected, treatment was performed with a recombinant tissue plasminogen activator (25 µg/0.1 cc) in the anterior chamber at the moment of the observation.

The Micromechanical Measuring Device. A sulcus-to-sulcus or intracapsular custom-sized micromechanical gauge was constructed for this study to enable the measurements of both force and movements existing either when placed at the sulcus or inside the capsular bag related to ciliary body pharmacological stimulation by using an internal spring capable of being compressed from 1.0 to 10.0 gram force (range: 0.01 to 0.1 N) according to Fisher5 and Wyatt6 analysis of the accommodation mechanics of the human eye. Similar force/movements gauges with different springs were successfully used in an earlier studies.9,10 The gauges were implanted in the primate eyes for 30 months with follow-up examinations every 3 months. All gauges included a 3.0-mm long spring held between two rigid surfaces (Figures 1A–1B). A metal pin with marks every 250 µm, protruding from the rear disc, passed via the center of the spring through a small hole in the front gauge surface. Pressurizing the discs against each other results in protrusion of the marked pin over the front disc surface (Figure 1A). The haptics of each gauge were custom made to accurately fit the anterior chamber of the implanted eye. The rigid construction of the gauge was needed to secure its accurate position and function over 30 months in the primate eyes.

The force gauge. (A) Fully compressed gauge demonstrating the marked center pin. (B) Fully relaxed gauge demonstrating the inner spring and the locking mechanism of the center pin.

Figure 1.

The force gauge. (A) Fully compressed gauge demonstrating the marked center pin. (B) Fully relaxed gauge demonstrating the inner spring and the locking mechanism of the center pin.

Measurement of the Ciliary Sulcus Forces Dynamics. Two months after implantation, all eyes were clear of inflammation. No evident synechia either posterior or anterior was evident in any case. Pupils were normally reactive to light even though some pupil ovaling was present in the cases where sulcus implantation of the measuring gauge had been performed. Using pharmacological stimulation, it was obligatory to provide full recovery time between the cycloplegic and cyclospasm stimuli. Each “session cycle” included pilocarpine 4% to induce cyclospasm and 2 weeks later cycloplegia was induced by cyclopentolate 1%. The measurements were taken at least 60 minutes after the pharmacological stimulation, with the whole process documented via a beam splitter by video camera attached to the slit lamp. The camera was focused on the marks on the center pin of the gauge with emphasis on the area where the pin intersected the front surface of the gauge. A cluster of images were isolated from the video sequence and analyzed with computer software (Adobe Photoshop; Adobe Systems, San Jose, CA) defining the accurate intersection with the front surface of the gauge (Figure 2) and enabling the calculation of the accurate travel distance of the pin as related to the induced pharmacological effect. The aspect of the haptics at the sulcus and the anatomical conditions found at that level were observed at 6 months and then every year with an endoscopic device (Endo Optiks, Little Silver, NJ) during the 5 years of the investigation.

(A) An isolated image of the gauge taken from a video sequence after pharmacological stimulation. The 250 µm marks on the pin are clear (thin left arrows) and the intersection of the pin with the gauge transparent surface is marked by a thicker (right) arrow (original magnification ×10). (B) Magnified image of the intersecting segment with accurate measurement of the intersect location (original magnification ×70).

Figure 2.

(A) An isolated image of the gauge taken from a video sequence after pharmacological stimulation. The 250 µm marks on the pin are clear (thin left arrows) and the intersection of the pin with the gauge transparent surface is marked by a thicker (right) arrow (original magnification ×10). (B) Magnified image of the intersecting segment with accurate measurement of the intersect location (original magnification ×70).

The primates were kept alive for a total of 5 years and then killed. All of the eyes were enucleated and dissected for morphological and pathology analysis.

Results

All surgeries were uneventful. Mild to moderate postoperative uveitic reaction developed in all eyes but responded well to single sub-Tenon injection of triamcinolone acetonide 10 mg (Kenalog; Bristol-Myers Squibb, Uxbridge, UK) in six animals and a second injection was needed in two animals.

The posterior capsule average movement (Table 1) between pharmacologically induced cycloplegia (Figure 3) and cyclospasm was 145 µm (range: 100 to 180 µm) and the average movement of the anterior capsule was 390 µm (range: 330 to 450 µm). The movement range of the in-the-bag gauges rapidly deteriorated to a standstill compared to the gradual deterioration of the on-the-bag gauges, in which 3 of 4 gauges retained a diminished but stable movement range after 30 months. At 15 months, massive intracapsular fibrosis packed the capsular bag from the inside, pressurizing the inner space of the gauge where the spring was positioned while casting solid in-the-bag gauges (Figure 4A). The measuring pins were attached to the gauge base surface and protruded through the gauge front surface while the marking on this part of the pin enabled reading of the distance between the two surfaces. The massive intracapsular fibrosis between these surfaces pushed them away from each other while pulling the measuring pin backward (Figure 4B). The on-the-bag gauges seem to be protected from direct fibrosis but the developing capsular contraction beneath them pressurized the contracting capsular interface onto the gauges, diminishing their movement range. Consequently, the measuring pin was gradually elevated at rest position over the anterior gauge surface (before pharmacological stimulation) as confirmed at the end of the study by morphological examination (Figure 5A). The data of this study suggest that the fibrotic process is stabilized 24 months after surgery (Table 1). It is noteworthy that 3 of 4 on-the-bag positioned gauges were still functional at approximately 25% of their initial range 30 months after surgery. The endoscopic study and the postmortem morphological observations of the dissected eyes with the on-the-bag gauges demonstrated posterior/anterior capsule adherence with minimal fibrosis underneath the gauge interface with the capsule (Figure 5B), whereas most of the fibrosis developed around the gauge edge toward the capsular periphery, in a typical Soemmering ring shape.

Capsular Fibrosis Effect on Gauge Movement Over Timea

Table 1:

Capsular Fibrosis Effect on Gauge Movement Over Time

The force gauge in the primate eye. (A) Cyclospasm using pilocarpine 4%. The contracted cilliary muscles relax the capsule and the internal spring pushes the pin inward as measured by the marks (arrows) above the gauge surface. (B) Cycloplegia using cyclopentolate 1%, following the relaxation of the ciliary muscles the pin is pushed outward by the stretched capsule as measured by the marks (arrows).

Figure 3.

The force gauge in the primate eye. (A) Cyclospasm using pilocarpine 4%. The contracted cilliary muscles relax the capsule and the internal spring pushes the pin inward as measured by the marks (arrows) above the gauge surface. (B) Cycloplegia using cyclopentolate 1%, following the relaxation of the ciliary muscles the pin is pushed outward by the stretched capsule as measured by the marks (arrows).

Dissected primate eye with in-the-bag gauge 30 months after implantation. (A) View from the vitreous side shows the massive fibrotic reaction inside the bag. (B) Top view of that gauge showing that fibrosis inflated the intracapsular space, pushing the gauge surfaces away from each other while pulling the measuring pin inward until stopped by the front surface of the gauge.

Figure 4.

Dissected primate eye with in-the-bag gauge 30 months after implantation. (A) View from the vitreous side shows the massive fibrotic reaction inside the bag. (B) Top view of that gauge showing that fibrosis inflated the intracapsular space, pushing the gauge surfaces away from each other while pulling the measuring pin inward until stopped by the front surface of the gauge.

Dissected primate eye with on-the-bag gauge 30 months after implantation. (A) Top view of the gauge showing that capsular contraction is pushing the gauge forward with the measuring pin stable high over the front gauge surface. (B) View from that gauge from the vitreous side revealed a Soemmering ring-like fibrosis around the gauge base.

Figure 5.

Dissected primate eye with on-the-bag gauge 30 months after implantation. (A) Top view of the gauge showing that capsular contraction is pushing the gauge forward with the measuring pin stable high over the front gauge surface. (B) View from that gauge from the vitreous side revealed a Soemmering ring-like fibrosis around the gauge base.

Discussion

During the past few decades cataract surgery has evolved into a highly successful surgical procedure providing outstanding visual rehabilitation for the patient and good refractive predictability of the outcome. Recently, spectacle independence at all distances is a target that has only been accomplished by multifocal intraocular lenses because other proposed accommodative lenses have failed or have been only partially successful.9 Nonetheless, the quest for restoring accommodation is supported by clinical evidence showing that the accommodative apparatus remains functional regardless of age or crystalline lens condition.3,4 The young natural crystalline “lens” is in fact an optomechanical device transforming the mechanical force of the ciliary muscles into optical power via a complex zonuli-capsular interface network. Only with the development of complete presbyopia is the natural crystalline lens reduced from an optomechanical device to a static thick lens. The ciliary muscles function throughout life within a range of 640 µm3,4 and quantified forces5–8 indicate that the mechanical apparatus of accommodation is working throughout life and recovery of its optical component might be possible by a optomechanical device.

The fundamental difference between restoring vision and restoring accommodation is the difference between static optics and dynamic optomechanical devices and therefore the first step toward restoring accommodation is by a conceptual shift from static “pure optics” solutions to dynamic optomechanical solutions. Both regular IOLs and accommodating IOLs must eventually sustain a direct interface, whether for mere positioning or complex optomechanical activation. Because even the smoothest cataract surgery represents a penetrating trauma to the eye, it initiates a capsular “healing” process in the form of fibrosis and contraction that is the functional nemesis of any biological or artificial implant with a totally unpredictable distribution and intensity that compromises the mechanical properties of the accommodating IOL/capsule interface.

Our primate model demonstrated the most devastating effect of capsular fibrosis on the capsular interface mechanics in eyes with in-the-bag positioned gauges. In these eyes fibrotic tissue proliferated onto the gauges as a casting material, while the capsule around them contracted as a shrinking cocoon (Figure 4), leading to complete physical stagnation of these gauges within 15 months of surgery. On-the-bag gauges were physically protected from the capsular fibrosis that was confined to the intracapsular space that was not pressurized by the gauge, assuming the shape of a Soemmering ring (Figure 5). Our findings indicated that a micromechanical gauge simulating accommodating IOL mechanics positioned on-the-bag is better protected from capsular fibrosis than an in-the-bag gauge. It was also noted that on-the-bag positioning enabled the gauges to maintain part of the initial functional capacity throughout the study, unlike in-the-bag gauges that were totally stagnant at 15 months postoperatively. These findings might have important implications in the future design and development of new models of accommodating IOLs aiming at the restoration of accommodation.

References

  1. Donders FC. On the anomalies of accommodation and refraction of the eye. London: The New Sydenham Society;1864.
  2. Duane A. Normal values of the accommodation at all agesJAMA. 1912;59:1010–1013. doi:10.1001/jama.1912.04270090254042 [CrossRef]
  3. Strenk SA, Semmlow JL, Strenk LM, Munoz P, Gronlund-Jacob J, DeMarco K. Age-related changes in human ciliary muscle and lens: a magnetic resonance imaging study. Invest Ophthalmol Vis Sci. 1999;40:1162–1169.
  4. Strenk SA, Strenk LM, Guo S. Magnetic resonance imaging of aging, accommodating, phakic, and pseudophakicciliary muscle diameters. J Cataract Refract Surg. 2006;32:1792–1798. doi:10.1016/j.jcrs.2006.05.031 [CrossRef]
  5. Fisher RF. The force of contraction of the human ciliary muscle during accommodation. J Physiol. 1977;270:51–74. doi:10.1113/jphysiol.1977.sp011938 [CrossRef]
  6. Wyatt HJ. Some aspects of the mechanics of accommodation. Vision Res. 1988;28:75–86. doi:10.1016/S0042-6989(88)80008-7 [CrossRef]
  7. Hermans EA, Dubbelman M, van der Heijde GL, Heethaar RM. Estimating the external force acting on the human eye lens during accommodation by finite element modeling. Vision Res. 2006;46:3642–3650. doi:10.1016/j.visres.2006.04.012 [CrossRef]
  8. Belaidi A, Pierscionek BK. Modeling internal stress distributions in the human lens: Can opponent theories coexist?J Vis. 2007;7:1–12. doi:10.1167/7.11.1 [CrossRef]
  9. Ben-Nun J, Alió LJ. Feasibility and development of a high-power real accommodating intraocular lens. J Cataract Refract Surg. 2005;31:1802–1808. doi:10.1016/j.jcrs.2005.06.037 [CrossRef]
  10. Ben-Nun J. The NuLens accommodating intraocular lens. Ophthalmol Clin North Am. 2006;1:129–134.

Capsular Fibrosis Effect on Gauge Movement Over Timea

Eye NumberPostoperative Months
2 to 35 to 68 to 911 to 1214 to 1517 to 1820 to 2123 to 2426 to 2730
Posterior capsule support
  1150110400000000
  21003000000000
  3180120500000000
  41501307040000000
Average gauge movements (µm)145974010000000
Anterior capsule support
  5400360300230200190130909090
  6450330210140100400000
  733030025022018014011010010090
  8380300220190150120120110110100
Average gauge movements (µm)39032224519516215790757570

10.3928/1081597X-20150122-08

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