**3.1. Definition**

allow students to practice in a safe environment, until they can perform the techniques at the expected level. Hypothesis that these models can shorten the learning curve, standardize training and assessment, became true. The results show that trainers using 3D printed models have done a lot to finish their tasks better and have a better learning experience than those who used only digital models or textbooks. This suggests that using 3D models enhances the understanding of anatomical structures, their collocations, and their relationships. With the advancement of 3D printing technology, the 3D print models can be made available to improve the training of young ophthalmologists in a simulated operating theater environ-

The development of 3D bioprinting technology, including the printing of living cells, different tissues, and even organs, is now becoming an important and expanding field of medical research. From 2012, this technology has been studied in academic circles and by biotechnology corporations (e.g., Organovo Co., San Diego, CA, USA) for possible use in tissue engineering applications, where tissues and organs are created by using 3D inkjet printing technology. The technology process is based on placing living cells onto a gel medium or sugar matrix and layer-by-layer predefined 3D structures are formed. In this way, blood vessels, bones, ears and other structures can be printed. Using 3D bioprinting technology in 2014, researchers successfully implemented a 3D skull component into a patient, with no adverse effects. This new technology represents an extension of the treatment options for creating and adapting personalized implants to the patient. The use of three-dimensional bioprinting in ophthalmology is, however, still limited, but for the generation of ocular tissues (e.g., conjunctiva, sclera, and corneas), the use of 3D bioprinting technology in the future

In the first place, the ophthalmologist must comprehend complicated anatomical structures of the eye globe and orbit and their connection with the suspected lesion. Structural relationships observed and defined between orbital structures, muscles, vessels, and nerves can be difficult to assess fully during the planning of the orbital surgery, based solely on the 2D scans obtained. The small surgical access field for eye globe (diameter 24 mm) also means that any mistake in navigating in this structures and complicated anatomy can have potentially devastating consequences for the patient—postradiation complications. Experience proves that, for both practical and educational purposes, the creation of an anatomically personalized organ models by using 3D printing technology is very useful. This technology allows a full appreciation of anatomical relationships and collocation between tumors or lesions and other complicated surrounding, but healthy structures. Advances in 3D printing technology enable the real prototyping of various anatomical structures and allow accurate representation of the patient's current state. In surgical or irradiation planning schemes in human medicine, it will be an invaluable aid to have this real 3D organ models.

ment, thus improving the training experience.

has a great potential.

158 3D Printing

**2.4. For surgical planning**

**2.3. For printing of live cells, tissues, and organs**

Intraocular melanoma is a quite rare type of cancer and is a disease in which tumor cells are formed in the part of the eye globe called the uvea (iris, ciliary body and choroid). Intermediate layer of the eye globe (uvea) contains melanocytes. Process of melanogenesis leads to produce melanin (can be found also in hair and in skin).

There are some cases in which doctors have detected intraocular melanoma during a routine eye globe examination. The chance of recovery depends on factors such as the size and cell type of the tumor. In support of classification, the staging system tumor node metastasis (TNM) is used for standardization of the tumors so the care teams can summarize information about how a tumor has spread. The information about the TNM classification is combined by a process called stage grouping. For example, intraocular melanoma grade T4 (due to classification) spreads to the orbit and extraocular tissues.

Uveal melanoma is relatively rare type of cancer, but the most common and most aggressive type of intraocular tumor in adults. The incidence of intraocular tumors varies from 0.2 to 1.0. Uveal melanoma mostly occurs in middle-aged people [7, 8].

#### **3.2. Signs and symptoms**

Most people with intraocular melanoma experience no symptoms of the disease in its early stages.

As the disease progresses, the following signs and symptoms can be seen:


Only in cases when there is a massive spread outside of the eye globe, there may be pain. If someone has any of the symptoms above, it is important to visit a doctor immediately so the cause can be found and treated.

pigment of the retina (e.g., drusen), atrophy patches and orange color change. These changes can occur not only in malignant but also in benign lesions. Choroidal melanoma may remain undetected under a great exudative retinal detachment or subretinal or vitreous bleeding.

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A rare occurrence of advanced choroidal melanoma results in a painful blind eye globe with cataracts and proptosis, resulting from tumor transscleral orbital enlargement. In anterior choroidal melanomas, sentinel vessels (dilated episcleral vessels visible through the conjunctiva) that nourish the metabolically active tumor may occur. Transscleral growing of the anterior choroidal melanoma (predominantly via the emission channels) can be identified during

In the case of eye globe tumors having a diameter greater than 2–3 mm, A-scan ultrasonography is suitable for diagnosis. The choroidal melanoma scan depicts a characteristic initial prominent spike, followed by low to moderate internal reflection with decreasing amplitude and significant echo. Vascular pulses can be seen as fine oscillations of the internal spiking model in the tumor area. Standard ultrasonography, currently used, has a diagnostic accuracy of more than 95%. Performing sequential A-scans with accurate dimensional measurements is a recommended complementary method after uncertain outcome of primary diagnostics. B-scan ophthalmological ultrasonography is performed routinely for the evaluation of any suspicious mass located in the posterior segment, especially in the patients with media opacity. For the diagnosis of choroidal melanomas, this method helps to determine not only the correct diagnosis, but also to evaluate possible extraocular enlargement, to estimate the size of the tumor after periodic recurrent observations, and to appropriately schedule a therapeutic intervention.

the examination as a small subconjunctival area of abnormal hyperpigmentation.

Intraocular melanomas have several characteristics as follows:

• An acoustic quiet zone at the base of the tumor called acoustic hollowing.

Ultrasound biomicroscopy (UBM) uses high-frequency waves. This method has excellent resolution and is therefore suitable for the diagnosis of anterior ocular abnormalities. It has ability to distinguish very frontal choroidal melanomas from those that originate from the ciliary body. Moreover, it can help define the frontal plane of the tumor or help to assess angle

In case of doubts, diagnostics of choroidal melanoma can be confirmed by fluorescein angiography or indocyanine green angiography, mostly in cases, when the lesions do not show

*3.4.1. Ultrasonography*

• Low-to-medium reflectivity.

• Excavation of underlying uveal tissue.

• Shadowing of subjacent soft tissues.

*3.4.2. Angiography and radiography*

• Internal vascularity.

closure glaucoma.

#### **3.3. Localization of uveal melanoma**

The localization of uveal melanoma is defined based on the area where the tumor is found in the eye globe and optionally based on the size of the tumor. The main localizations of the intraocular melanoma include the following tumors due to anatomical localization:


In certain cases, intraocular melanoma can be complicated by extraocular extension. The most frequent metastases of uveal melanoma are in the liver.

#### **3.4. Diagnostic methods**

Slit lamp examination, ophthalmoscopy and fund us photo documentation are basic examination methods.

Melanomas from choroidea can vary from dark pigmented to amelanotic, some even partially pigmented. Small choroidal melanomas are characteristic with a typical shape, where the mass under the retinal pigment epithelium is nodular, dome-shaped and well-defined. During the growth of choroidal melanoma, more irregular configurations and shapes, such as bilobular, multilobular or spongy are observed. Diffuse choroidal melanoma, whose lateral growth in choroids with minimal elevation is a characteristic feature, it is more difficult to make a diagnosis. In many cases, the diffuse choroidal melanoma causes significant exudative retinal detachment.

If the tumor is lightly pigmented, then its abnormal vascularization can usually be detected by ophthalmoscope. Excessive choroidal melanomas usually cause changes in the epithelial

**Figure 1.** Enucleated eye globe with intraocular tumor—arrows shows the tumor mass (choroidal melanoma).

pigment of the retina (e.g., drusen), atrophy patches and orange color change. These changes can occur not only in malignant but also in benign lesions. Choroidal melanoma may remain undetected under a great exudative retinal detachment or subretinal or vitreous bleeding.

A rare occurrence of advanced choroidal melanoma results in a painful blind eye globe with cataracts and proptosis, resulting from tumor transscleral orbital enlargement. In anterior choroidal melanomas, sentinel vessels (dilated episcleral vessels visible through the conjunctiva) that nourish the metabolically active tumor may occur. Transscleral growing of the anterior choroidal melanoma (predominantly via the emission channels) can be identified during the examination as a small subconjunctival area of abnormal hyperpigmentation.

#### *3.4.1. Ultrasonography*

Only in cases when there is a massive spread outside of the eye globe, there may be pain. If someone has any of the symptoms above, it is important to visit a doctor immediately so the

The localization of uveal melanoma is defined based on the area where the tumor is found in the eye globe and optionally based on the size of the tumor. The main localizations of the

In certain cases, intraocular melanoma can be complicated by extraocular extension. The most

Slit lamp examination, ophthalmoscopy and fund us photo documentation are basic examina-

Melanomas from choroidea can vary from dark pigmented to amelanotic, some even partially pigmented. Small choroidal melanomas are characteristic with a typical shape, where the mass under the retinal pigment epithelium is nodular, dome-shaped and well-defined. During the growth of choroidal melanoma, more irregular configurations and shapes, such as bilobular, multilobular or spongy are observed. Diffuse choroidal melanoma, whose lateral growth in choroids with minimal elevation is a characteristic feature, it is more difficult to make a diagnosis. In many cases, the diffuse choroidal melanoma causes significant exudative retinal detachment. If the tumor is lightly pigmented, then its abnormal vascularization can usually be detected by ophthalmoscope. Excessive choroidal melanomas usually cause changes in the epithelial

**Figure 1.** Enucleated eye globe with intraocular tumor—arrows shows the tumor mass (choroidal melanoma).

intraocular melanoma include the following tumors due to anatomical localization:

cause can be found and treated.

160 3D Printing

• Melanoma of the iris.

• Ciliary body melanoma.

**3.4. Diagnostic methods**

tion methods.

• Choroidal melanoma (**Figure 1**).

frequent metastases of uveal melanoma are in the liver.

**3.3. Localization of uveal melanoma**

In the case of eye globe tumors having a diameter greater than 2–3 mm, A-scan ultrasonography is suitable for diagnosis. The choroidal melanoma scan depicts a characteristic initial prominent spike, followed by low to moderate internal reflection with decreasing amplitude and significant echo. Vascular pulses can be seen as fine oscillations of the internal spiking model in the tumor area. Standard ultrasonography, currently used, has a diagnostic accuracy of more than 95%. Performing sequential A-scans with accurate dimensional measurements is a recommended complementary method after uncertain outcome of primary diagnostics.

B-scan ophthalmological ultrasonography is performed routinely for the evaluation of any suspicious mass located in the posterior segment, especially in the patients with media opacity. For the diagnosis of choroidal melanomas, this method helps to determine not only the correct diagnosis, but also to evaluate possible extraocular enlargement, to estimate the size of the tumor after periodic recurrent observations, and to appropriately schedule a therapeutic intervention.

Intraocular melanomas have several characteristics as follows:


Ultrasound biomicroscopy (UBM) uses high-frequency waves. This method has excellent resolution and is therefore suitable for the diagnosis of anterior ocular abnormalities. It has ability to distinguish very frontal choroidal melanomas from those that originate from the ciliary body. Moreover, it can help define the frontal plane of the tumor or help to assess angle closure glaucoma.

#### *3.4.2. Angiography and radiography*

In case of doubts, diagnostics of choroidal melanoma can be confirmed by fluorescein angiography or indocyanine green angiography, mostly in cases, when the lesions do not show pathogenic symptoms. Fluorescein angiographic changes, which can be observed in small choroidal melanomas, may be similar to some choroidal nevi. Such changes range from normal angiography findings to hypofluorescence developed secondary to blockage of the background fluorescence. In larger melanomas, a patchy pattern of early hyper- and hypofluorescence may occur, which can be followed by late intense staining. In some cases, choroidal melanomas can develop their own internal vascularization so that appear on the angiogram. Simultaneous fluorescence of the choroidal and retinal circulation in the tumor is an angiographic feature, called the "double circulation model." Its occurrence differs from choroidal melanomas.

**3.5. Treatment opportunities**

therapeutical methods are used.

tering one fraction [9–11].

The important prognostic indicators they initiate the following therapy for posterior uveal melanoma are the age and the volume (size) of the tumor. Many studies are documenting that over 50% of patients with uveal melanoma die because of direct or indirect reasons (e.g., metastasis) within 15 years after the therapy, although radical surgery (enucleation) or other

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In turn, modern diagnostic tools, they include ophthalmological examination, CT, and MRI brought most vital advances in the ability of primary uveal melanoma diagnosis. The diagnostic methods have radically improved in the last decades, and different types of radio surgery (external beam, charged particle or brachytherapy) have become the preferred treatment in significant number of patients with uveal melanoma. One of the main reasons for the development of alternative therapies is the objective of promoting survival and maintaining vision in patients who have experienced uveal melanoma. Among other things, many types of radiation are used in today's treatment of posterior uveal melanoma. One of the representatives of the "conservative"

In addition to SRS, the gamma-knife radiosurgery method is used. Both methods provide good local control with survival rates comparable to other treatments. SRS of extracerebral lesions, such as uveal melanoma, has been invented about 20 years ago. An alternative treatment that has been proven to treat middle and large posterior choroidal melanoma is the SRS method. Another method is the plaque radiotherapy, when the eye globe salvation is achieved. It is used especially in cases of tumor location outside the optical disc or the macula. The positive consequence for the patient is the useful vision that can be retained after treatment. Linear accelerator therapy with a single fraction of the intraocular tumor is considered to be a relatively unusual approach to the treatment of uveal melanoma. For treatment planning coordinates is used an image fusion of a contrast-enhanced MRI and CT. When using a collimation system in an operation, it is important to achieve spatial accuracy when adminis-

Stereotactic radiosurgery was initially developed in 1949 by Lars Leksell, the Swedish neurosurgeon, who treated small targets of tumors located in the brain. It was a new step in radiotherapy methods. Nowadays, the stereotactic radiosurgery (or external beam irradiation with protons or helium ions) is a regularly used option in the treatment of mainly medium-sized choroidal melanomas. In many cases, it has been applied for larger tumors. Eye globe and orbit scanning by CT or MRI is necessary for verifying of extraocular extension. It is necessary to use these techniques to differentiate between choroidal tumor and primary versus secondary retinal detachment. Every patient with a medium-sized melanoma is sent to chest X-ray, liver ultrasound, and general examination but also to PET/CT to detect possible metastases. Methods like MRI, CT and also digital subtraction angiography (DSA) are included in imaging equipment. Structures of the eye globe and lesions are defined, visualized and localized.

approach is stereotactic radiosurgery (SRS) with the usage of a linear accelerator.

**4. Stereotactic radiosurgery for intraocular tumors**

#### *3.4.3. Computed tomography*

Computer tomography (CT) imaging method is more expensive and less sensitive compared to ultrasonography. However, it is used for scanning of the eye globe and orbit due to its ability to visualize extraocular tumor growth and to help distinguish between choroid or retinal detachment and solid tumor.

Prior to this examination, application of intravenous injection of the contrast agent is needed. As a result, contrast will cause enhancement of choroidal melanoma, whereas in case of exudation will not.

#### *3.4.4. Magnetic resonance imaging*

Magnetic resonance imaging (MRI), also used for scanning the eye globe and orbit, is even more expensive than CT scanning and less sensitive than ultrasound. However, MRI uses surface coil imaging and gadolinium as a contrast material for improving its resolution. Within the MRI, high-density lesions represent T1-stage pigmented melanomas, and low density can exhibit pigmented melanoma at T2 stage. In many cases, MRI is used to determine the extrascleral melanoma enlargement or to distinguish surrounding fluid from the tumor.

#### *3.4.5. Biopsy and genetic analysis*

Practice usually does not require the use of a fine needle biopsy and an incisional biopsy. However, these additional examination methods may be useful in differential diagnosis. They are used to distinguish amelanotic melanomas from metastatic tumors and as complementary tests, if the results of other tests are ambiguous. It is possible to achieve more than 95% accuracy in tumors larger than 3 mm using both types of biopsy. Comparing both methods, incisional biopsy is more invasive and comes with higher complications rate, but has lower rate of falsely positive or negative results. Intralesional or perilesional hemorrhage are the most common complications, a fine needle biopsy is not connected with higher risk of spreading cancer cells in the case of choroidal melanoma.

Following biopsy, the prompt treatment is indicated with an aim to prevent extrascleral extension.

Nowadays, genetic analysis and karyotyping of biopsy samples are becoming more important. Various studies have documented that Chromosome 3 monosomy in the choroidal tumor is associated with a significantly higher risk of developing metastatic process. Nowadays, sadly, there is still no effective treatment for metastatic disease available.

#### **3.5. Treatment opportunities**

pathogenic symptoms. Fluorescein angiographic changes, which can be observed in small choroidal melanomas, may be similar to some choroidal nevi. Such changes range from normal angiography findings to hypofluorescence developed secondary to blockage of the background fluorescence. In larger melanomas, a patchy pattern of early hyper- and hypofluorescence may occur, which can be followed by late intense staining. In some cases, choroidal melanomas can develop their own internal vascularization so that appear on the angiogram. Simultaneous fluorescence of the choroidal and retinal circulation in the tumor is an angiographic feature, called the "double circulation model." Its occurrence differs from choroidal melanomas.

Computer tomography (CT) imaging method is more expensive and less sensitive compared to ultrasonography. However, it is used for scanning of the eye globe and orbit due to its ability to visualize extraocular tumor growth and to help distinguish between choroid or retinal

Prior to this examination, application of intravenous injection of the contrast agent is needed. As a result, contrast will cause enhancement of choroidal melanoma, whereas in case of exudation

Magnetic resonance imaging (MRI), also used for scanning the eye globe and orbit, is even more expensive than CT scanning and less sensitive than ultrasound. However, MRI uses surface coil imaging and gadolinium as a contrast material for improving its resolution. Within the MRI, high-density lesions represent T1-stage pigmented melanomas, and low density can exhibit pigmented melanoma at T2 stage. In many cases, MRI is used to determine the extra-

Practice usually does not require the use of a fine needle biopsy and an incisional biopsy. However, these additional examination methods may be useful in differential diagnosis. They are used to distinguish amelanotic melanomas from metastatic tumors and as complementary tests, if the results of other tests are ambiguous. It is possible to achieve more than 95% accuracy in tumors larger than 3 mm using both types of biopsy. Comparing both methods, incisional biopsy is more invasive and comes with higher complications rate, but has lower rate of falsely positive or negative results. Intralesional or perilesional hemorrhage are the most common complications, a fine needle biopsy is not connected with higher risk of spread-

Following biopsy, the prompt treatment is indicated with an aim to prevent extrascleral extension. Nowadays, genetic analysis and karyotyping of biopsy samples are becoming more important. Various studies have documented that Chromosome 3 monosomy in the choroidal tumor is associated with a significantly higher risk of developing metastatic process. Nowadays, sadly,

scleral melanoma enlargement or to distinguish surrounding fluid from the tumor.

*3.4.3. Computed tomography*

detachment and solid tumor.

*3.4.4. Magnetic resonance imaging*

*3.4.5. Biopsy and genetic analysis*

ing cancer cells in the case of choroidal melanoma.

there is still no effective treatment for metastatic disease available.

will not.

162 3D Printing

The important prognostic indicators they initiate the following therapy for posterior uveal melanoma are the age and the volume (size) of the tumor. Many studies are documenting that over 50% of patients with uveal melanoma die because of direct or indirect reasons (e.g., metastasis) within 15 years after the therapy, although radical surgery (enucleation) or other therapeutical methods are used.

In turn, modern diagnostic tools, they include ophthalmological examination, CT, and MRI brought most vital advances in the ability of primary uveal melanoma diagnosis. The diagnostic methods have radically improved in the last decades, and different types of radio surgery (external beam, charged particle or brachytherapy) have become the preferred treatment in significant number of patients with uveal melanoma. One of the main reasons for the development of alternative therapies is the objective of promoting survival and maintaining vision in patients who have experienced uveal melanoma. Among other things, many types of radiation are used in today's treatment of posterior uveal melanoma. One of the representatives of the "conservative" approach is stereotactic radiosurgery (SRS) with the usage of a linear accelerator.

In addition to SRS, the gamma-knife radiosurgery method is used. Both methods provide good local control with survival rates comparable to other treatments. SRS of extracerebral lesions, such as uveal melanoma, has been invented about 20 years ago. An alternative treatment that has been proven to treat middle and large posterior choroidal melanoma is the SRS method. Another method is the plaque radiotherapy, when the eye globe salvation is achieved. It is used especially in cases of tumor location outside the optical disc or the macula. The positive consequence for the patient is the useful vision that can be retained after treatment. Linear accelerator therapy with a single fraction of the intraocular tumor is considered to be a relatively unusual approach to the treatment of uveal melanoma. For treatment planning coordinates is used an image fusion of a contrast-enhanced MRI and CT. When using a collimation system in an operation, it is important to achieve spatial accuracy when administering one fraction [9–11].
