**4. Diagnosis and treatment**

is separated in three layers: the lipid layer, which protects the tear against evaporation and is secreted by Moll, Meibomian, and Zeiss glands [1]; the mucin layer produced by Manz glands, Henle crypts, and corneal and conjunctival cells—this one stays between the hydrophobic ocular surface and the hydrophilic tear film [2]; and the last and the most prevalent layer, the aque-

The most recent definition of dry eye is that it is a multifactorial disease of the tears and ocular surface, which is accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles [4]. The inflammation of the ocular surface can be both the cause and the consequence of dry eye: dysfunction of the lacrimal glands alters the tear composition, leading to hyperosmolarity that stimulates more inflammation [5], and another factor recognized

There are several risk factors for dry eye, all of them are controversial. These are female sex, menopause therapy, omega-3 deficiency, refractive surgeries; use of some medications as antihistaminic drugs, antihypertensive drugs, diuretics, antidepressants, and others; hepatitis C; radiation therapy; Asian race; HIV and HTLV infection; chemotherapy; isotretinoic acid use; large facetectomy incisions; low humidity environments; ovarian dysfunction; and sarcoidosis [7].

This disease is actually classified into two primary categories: these are tear-deficient and evaporative categories. The tear-deficient dry eye group generally can be due to Sjogren's syndrome or non-Sjogren's syndrome. Sjogren's syndrome is an exocrinopathy in which lacrimal secretion deficiency occurs due to an autoimmune process that affects the lacrimal glands, salivary glands, and other organs of the body [8]. Non-Sjogren's syndrome is caused by lacrimal diseases or lacrimal obstruction and by reflex alterations, without autoimmune factor role. Some causes are age-related dry eye, congenital alacrima, familial dysautonomia, sarcoidosis, lymphoma, AIDS (acquired immunodeficiency disease syndrome), gland denervation, lacrimal obstruction as in pemphigus, trigeminal injury, diabetes, neurotrophic keratopathy, use of contact lenses, and motor reflex block due to VII pair injury [9, 10]. The evaporative causes of dry eye disease are due to oil deficit, lid changes, use of contact lenses, or ocular surface diseases, as allergic conjunctivitis, and some of the iatrogenic dry eye that occurs after the use

of systemic or topical medications or after surgeries or nonsurgical procedures [8, 11].

Dry eye can be also classified according to severity. One of the schemes is proposed by Delphi Panel [8, 12]. This classification in grades 1–4 (mild to severe) is based on the frequency or intensity of the dry eye symptoms and discomfort, the blurred vision and visual symptoms, conjunctival injection or redness, conjunctival staining, corneal staining, changes in the cornea and tear as in ocular surface, alterations in the glands and lids, tear film break-up time

Dry eye disease affects from 5 to 50% of population; this discrepancy is probably observed due to the absence of a consensus on the diagnosis of dry eye and the lack of standardization

ous layer, produced by Wolfring and Krause glands [3].

22 Plasma Medicine - Concepts and Clinical Applications

in dry eye pathogenesis is oxidative stress [6].

(TFBUT), and Schirmer's test values.

**3. Epidemiology**

Diagnosis is controversial, and literature shows the lack of correlation between some objective tests and symptoms; this is probably due to the difficulty in understanding dry eye pathophysiology [16].

There are some guidelines in this theme, and one of them is the American Academy of Ophthalmology that relates that dry eye diagnosis is obtained after a clinical approach that include asking the patient about exposition to dry eye risk factors and the most common symptoms and signs like redness, itching, photophobia, dryness, foreign body sensation, or pain. It is also important to ask the patient about the exposition to some kind of pollutant, if he is a smoker, if he has any systemic disease (like dermatological, allergic, or rheumatic diseases), checking the hygiene of eyelashes and eyelids, use of medications, eyedrop use, previous ocular surgeries [17], and use of a screening questionnaire as the OSDI (Ocular Surface Disease Index) [18]. The clinical history is followed by a complete ophthalmological exam, including evaluating the eyelids, skin, nerves, visual acuity, and biomicroscopy, and some specific tests like tear breakup time, tear film osmolarity determination, and ocular surface staining with fluorescein lissamine green [4]. The assessment of the tear meniscus (less than 0.35 mm is abnormal) can be performed, verifying if the blink rate is decreased and evaluate the quality of the tear (if there are mucus and debris) and corneal topography [3].

Management of dry eye disease will depend on the cause of this condition and its severity. There is currently no cure for dry eye, and any causal factors that are amenable to treatment should be treated. It includes modifications of the environment; suspension of topical or systemic medications, associated with worsening when possible; artificial tear lubrification; and eyelid hygiene [19].

Generally, the conventional treatment is the lubricants, but it does not resolve all the cases. There are a wide variety of artificial tears, like 1% sodium hyaluronate, hypotonic solutions, those that contains lipids or substances with bioadhesive properties and formulas that have substances that protects the cell's stress; but none of them has the natural tear properties [20, 21].

Other therapies are topical cyclosporine and corticosteroids [22], but these have some disadvantages such as eye irritation and ocular pressure elevation and cataract, respectively [23, 24]. In moderate cases we can also use systemic supplements with omega-3 and linoleic acids and the increased consumption of water, lacrimal occlusion, and glasses use. In severe dry eye, in addition to all these treatments, we can take another measure like systemic cholinergic agonists, systemic anti-inflammatory agents, mucolytic agents, contact lenses, correction of palpebral alterations, permanent lacrimal punctal occlusion, tarsorrhaphy, and, finally, the autologous serum tears [17].

with the production of mucin 1 by some conjunctival cells. Transforming growth factor b1 (TGF-b1) has an increased levels in the epithelium during corneal stromal repair processes; it stimulates the production of collagen, fibronectin, and proteoglycans and together with the platelet-derived growth factor (PDGF) has an important anti-inflammatory action [49]. Vitamin A is one of the major epitheliotropic factors in autologous serum; it is 100 times more

The Use of Platelet-Rich Plasma in Dry Eye Disease http://dx.doi.org/10.5772/intechopen.76090 25

Fibronectin is an important protein to corneal reepithelization, promoting healing and phagocytosis [51]. Annexin A5 has been investigated as an alternative to fibronectin eyedrops. It interacts with some integrins and stimulates the secretion of plasminogen activator-type urokinase, whose expression is increased in epithelial defects. Albumin is one of the most important proteins in the blood. It reduces the natural degradation of cytokines and growth factors in areas of tissue injury and shows antiapoptopic activity [39, 52, 53]. Alpha-2-macroglobulin neutralizes proteolytic enzymes. It is useful in ocular burns and marginal ulcers [32, 39]. Fibroblast growth factor-beta is a factor that promotes corneal healing, increasing cell prolif-

The insulin-like growth factor helps epithelial cell migration [55]. Neural growth factor (NGF) is the most well-known neurotrophin. It restores the function of injured neurons and can be

One of the PRP advantages is that it has not cytokines derived from leucocytes and monocytes, which are present in autologous serum and can be deleterious in patients with immune diseases [57]. PRP also regulates expression of several genes in the cellular differentiation improving biological activity of the corneal epithelial cells when compared with autologous serum [58]. The PRP protects the ocular surface from scar formation more than autologous serum, because of reduction of myofibroblasts. It has been observed in PRK where patients who had done this surgery has a decreased incidence of haze [59]. PRP causes reduction in inflammation by indirect action, through the reduction of osmolarity, thus, diluting the pro-inflammatory factors existing in the ocular surface. This also occurs because of the presence of the growth factorrich plasma interleukin-1 receptor antagonist as well as the presence of metalloproteinase [60]. Platelets have a lot of important functions that are repairing tissue damage; coagulation prevents blood loss, secreting proteins, cytokines, and other mediators; inducing tissue regeneration by cell migration, proliferation, and angiogenesis, and preventing infections because of

its antibiotic action. They also have an anti-inflammatory and analgesic action [61].

Platelet-rich plasma has been used in several medical and dental areas. The platelet-rich plasma has approximately 1 million/ml platelets [62], and it has been used to the revitalization of necrotic pulp teeth [63], in periodontitis [64], in revascularization of young teeth [65],

Platelet-rich plasma has been used in orthopedic therapies like cartilage repair [67], also in

bone regeneration, and in tendons, ligaments, and articular lesions [68].

**5. The use of PRP in medicine and odontology**

concentrated than in natural tear and prevents squamous epithelial metaplasia [50].

eration and motility [54].

effective in trophic ulcers [56].

and in other oral conditions [66].

The Ebers Papyrus 1534 BC is the first reference in the history of a blood derivative in the eye. In 1975, Ralph et al. used it in dry eye [25]. Fox et al. and later Tsubota related the use of autologous serum as an alternative treatment of severe dry eye cases [26, 27]. During many years of study, fetal bovine serum, allogenic serum, and umbilical cord serum have been used; however, they are heterologous, the risks of infections or allergic reactions are increased, and their use is not possible in any center [28]. It does not have preservative, and it is rich in vitamins, fibronectin, growth factors, and cytokines and has biomechanical properties similar to natural tear film, and they do not have preservative which is common in artificial tears [29]. Epidermal growth factors and vitamin A are important for proliferation, differentiation, and maturation of the ocular surface epithelium [30]. Fibroblast growth factor-beta is also involved in epithelial healing, fibronectin promotes cell migration, albumin has antiapoptopic activity, alpha-2-macroglobulin has anti-collagenase action, platelet-derived growth factor promotes hepatocytes growth factor, and substance P and insulin-like growth factor aid in the migration and adhesion of epithelium to the stroma [31]. The serum also maintains intracellular ATP at acceptable levels and cell membrane integrity [32–35].

Some authors related the use of autologous serum drops in dry eye with some promisor results [35, 36].

Kojima et al. in 2005 described increased TFBUT in treated group comparing to control group (using artificial tears) [37]. Lee and Chen studied the use of autologous serum in 23 patients by 18 months and found improvements in symptoms and corneal staining pattern in approximately 75% of patients [38].

Other indications for the use of autologous serum have been the epithelial defects [39], graftversus-host disease [40], neurotrophic keratopathy [41], trabeculectomy ampoules [42], after refractive surgery [43, 44], Mooren's ulcer [45], and other keratitis [46].

Tananuvat et al., in a randomized prospective study, found that control eyes had improvement in symptoms, signs, and rose bengal staining compared with the baseline. However, some advantages neither Schirmer's test results nor tear breakup time improved in treated group [34].

Urzua et al. described in a double-blind crossover clinical trial 12 severe dry eye syndrome patients in which autologous serum treatment showed a statistically significant higher OSDI decrease (50%) versus conventional treatment (22%). There were no significant changes in objective parameters (Oxford corneal staining and TBUT) [47]. A review to evaluate autologous serum efficacy compared to lubricants, in dry eye disease, concluded that there is a great heterogeneity considering the preparation and storage of the eyedrops, as well as the adequate use of this therapy, and that new studies that standardize these items would be necessary [19].

Another alternative, platelet-rich plasma (PRP), can be used in severe dry eye. It is prepared in double centrifugation of total plasma. Some of the important growth factors this hemoderivate has are platelet-derived angiogenesis factor, platelet-derived epithelial growth factor, and platelet factor 4 [48].

The epidermal growth factor accelerates the healing process and epithelial migration in the cornea, besides stimulating the DNA synthesis of the epithelial cells, and is also associated with the production of mucin 1 by some conjunctival cells. Transforming growth factor b1 (TGF-b1) has an increased levels in the epithelium during corneal stromal repair processes; it stimulates the production of collagen, fibronectin, and proteoglycans and together with the platelet-derived growth factor (PDGF) has an important anti-inflammatory action [49]. Vitamin A is one of the major epitheliotropic factors in autologous serum; it is 100 times more concentrated than in natural tear and prevents squamous epithelial metaplasia [50].

palpebral alterations, permanent lacrimal punctal occlusion, tarsorrhaphy, and, finally, the

The Ebers Papyrus 1534 BC is the first reference in the history of a blood derivative in the eye. In 1975, Ralph et al. used it in dry eye [25]. Fox et al. and later Tsubota related the use of autologous serum as an alternative treatment of severe dry eye cases [26, 27]. During many years of study, fetal bovine serum, allogenic serum, and umbilical cord serum have been used; however, they are heterologous, the risks of infections or allergic reactions are increased, and their use is not possible in any center [28]. It does not have preservative, and it is rich in vitamins, fibronectin, growth factors, and cytokines and has biomechanical properties similar to natural tear film, and they do not have preservative which is common in artificial tears [29]. Epidermal growth factors and vitamin A are important for proliferation, differentiation, and maturation of the ocular surface epithelium [30]. Fibroblast growth factor-beta is also involved in epithelial healing, fibronectin promotes cell migration, albumin has antiapoptopic activity, alpha-2-macroglobulin has anti-collagenase action, platelet-derived growth factor promotes hepatocytes growth factor, and substance P and insulin-like growth factor aid in the migration and adhesion of epithelium to the stroma [31]. The serum also maintains intra-

Some authors related the use of autologous serum drops in dry eye with some promisor

Kojima et al. in 2005 described increased TFBUT in treated group comparing to control group (using artificial tears) [37]. Lee and Chen studied the use of autologous serum in 23 patients by 18 months and found improvements in symptoms and corneal staining pattern in approxi-

Other indications for the use of autologous serum have been the epithelial defects [39], graftversus-host disease [40], neurotrophic keratopathy [41], trabeculectomy ampoules [42], after

Tananuvat et al., in a randomized prospective study, found that control eyes had improvement in symptoms, signs, and rose bengal staining compared with the baseline. However, some advantages neither Schirmer's test results nor tear breakup time improved in treated group [34]. Urzua et al. described in a double-blind crossover clinical trial 12 severe dry eye syndrome patients in which autologous serum treatment showed a statistically significant higher OSDI decrease (50%) versus conventional treatment (22%). There were no significant changes in objective parameters (Oxford corneal staining and TBUT) [47]. A review to evaluate autologous serum efficacy compared to lubricants, in dry eye disease, concluded that there is a great heterogeneity considering the preparation and storage of the eyedrops, as well as the adequate use of this therapy, and that new studies that standardize these items would be necessary [19]. Another alternative, platelet-rich plasma (PRP), can be used in severe dry eye. It is prepared in double centrifugation of total plasma. Some of the important growth factors this hemoderivate has are platelet-derived angiogenesis factor, platelet-derived epithelial growth factor,

The epidermal growth factor accelerates the healing process and epithelial migration in the cornea, besides stimulating the DNA synthesis of the epithelial cells, and is also associated

cellular ATP at acceptable levels and cell membrane integrity [32–35].

refractive surgery [43, 44], Mooren's ulcer [45], and other keratitis [46].

autologous serum tears [17].

24 Plasma Medicine - Concepts and Clinical Applications

results [35, 36].

mately 75% of patients [38].

and platelet factor 4 [48].

Fibronectin is an important protein to corneal reepithelization, promoting healing and phagocytosis [51]. Annexin A5 has been investigated as an alternative to fibronectin eyedrops. It interacts with some integrins and stimulates the secretion of plasminogen activator-type urokinase, whose expression is increased in epithelial defects. Albumin is one of the most important proteins in the blood. It reduces the natural degradation of cytokines and growth factors in areas of tissue injury and shows antiapoptopic activity [39, 52, 53]. Alpha-2-macroglobulin neutralizes proteolytic enzymes. It is useful in ocular burns and marginal ulcers [32, 39]. Fibroblast growth factor-beta is a factor that promotes corneal healing, increasing cell proliferation and motility [54].

The insulin-like growth factor helps epithelial cell migration [55]. Neural growth factor (NGF) is the most well-known neurotrophin. It restores the function of injured neurons and can be effective in trophic ulcers [56].

One of the PRP advantages is that it has not cytokines derived from leucocytes and monocytes, which are present in autologous serum and can be deleterious in patients with immune diseases [57]. PRP also regulates expression of several genes in the cellular differentiation improving biological activity of the corneal epithelial cells when compared with autologous serum [58].

The PRP protects the ocular surface from scar formation more than autologous serum, because of reduction of myofibroblasts. It has been observed in PRK where patients who had done this surgery has a decreased incidence of haze [59]. PRP causes reduction in inflammation by indirect action, through the reduction of osmolarity, thus, diluting the pro-inflammatory factors existing in the ocular surface. This also occurs because of the presence of the growth factorrich plasma interleukin-1 receptor antagonist as well as the presence of metalloproteinase [60].

Platelets have a lot of important functions that are repairing tissue damage; coagulation prevents blood loss, secreting proteins, cytokines, and other mediators; inducing tissue regeneration by cell migration, proliferation, and angiogenesis, and preventing infections because of its antibiotic action. They also have an anti-inflammatory and analgesic action [61].
