Autologous platelet-rich plasma eye drop versus artificial tear eye drop for symptomatic dry eye disease: A prospective comparative interventional study

Abstract

Purpose:

To evaluate and compare the efficacy of autologous platelet-rich plasma (aPRP) eye drop and artificial tear (AT) eye drop in moderate to severe symptomatic dry eye disease (DED).

Methods:

This prospective interventional study included 121 eyes of 61 patients of moderate to severe DED. Patients were divided into aPRP (31 patients) and AT (30 patients) group. Ocular Surface Disease Index (OSDI) score, tear film breakup time (TBUT) (s), corneal fluorescein staining (CFS) score, and Schirmer test score (mm) of both the groups were evaluated and compared pre-treatment and post-treatment at the end of 3 months.

Results:

The mean age of the aPRP group and AT group was 52.8 ± 12.8 years and 55.5 ± 13.4 years, respectively. At the end of 3 months, OSDI score reduced more in the aPRP group as compared to AT group, and the mean difference (−22.7) was statistically significant (P < 0.001). There was no significant difference in post-treatment Schirmer test score between the two groups (P = 0.44). Post-treatment improvement in TBUT and CFS score in the aPRP group was significantly higher in the aPRP group as compared to that in the AT group (P < 0.05). Bruising at the site of blood withdrawal was noted in two patients in the aPRP group.

Conclusion:

aPRP is safe and more effective than AT in treating patients with moderate to severe symptomatic DED.

Dry eye disease (DED) is a multifactorial disease of the ocular surface with tear film instability, hyperosmolarity, and ocular surface inflammation.[1] Tear film plays an important role in maintaining the health of the ocular surface.[2] Tear film contains various essential components, including epidermal growth factors, vitamin A, hepatocyte growth factor, fibronectin, and neurotrophic growth factor. These growth factors are associated with the regulation of proliferation, differentiation, and maturation of ocular surface epithelium.[3,4] Imbalance in these growth factors may be responsible for the pathogenesis of DED.[5]

Detection and treatment of dry eye is important as patients are very prone to potentially blinding infections, such as bacterial keratitis,[5] and are at an increased risk of complications following common procedures such as laser refractive surgery. Various treatment modalities are available for the treatment of DED, including artificial tear substitutes, anti-inflammatory agents, immune-suppressants, and punctal plugs. Autologous blood derivatives are newer modalities of dry eye treatment.

The initial reports of the efficacy of autologous serum for the treatment of dry eye promoted interest in the search for an ideal tear substitute.[6] The ensuing research not only corroborated the efficacy of autologous serum for the treatment of a variety of pathologies of the ocular surface[7,8,9] but also stimulated newer applications of blood derivatives in ophthalmology. In recent years, further progress has been made by including the factors derived from platelets in the composition of a novel blood derivative, that is, plasma rich in growth factors (PRGF).[10] This product is being successfully applied in various medical areas, such as maxillofacial surgery, traumatology, dermatology, orthopedics, and gynecology.[11,12] More recently, its application in ophthalmology for the treatment of persistent epithelial defects has been reported.[13,14]

PRP is a newer treatment modality with abundant growth factors, bacteriostatic nature, anti-apoptotic, and anti-collagenase property. It is seen to be very effective in treating dry eye not amenable to treatment by other means. It can be autologous or heterologous. Autologous PRP has added benefits of preventing occurrence of allergy or immunological reactions that may occur in cases of heterologous donation.

Methods

The present study was conducted on 121 eyes (61 patients) of symptomatic moderate to severe dry eye in a tertiary care center of central India from March 2021 to August 2021. The study protocol was approved by the ethical review committee, and the study was performed in accordance to the tenets of Declaration of Helsinki. The study has been registered in Clinical Trial Registry-India (CTRI/2021/03/031887). A written informed voluntary consent was taken from all the study subjects after explaining the nature and possible consequences of the trial. All patients underwent standard ocular examination protocol. Patients were divided into two groups: aPRP (autologous platelets rich plasma) group and AT (artificial tear) group. The aPRP group was treated with 20% autologous PRP eye drops 4–6 times a day for 3 months. The AT group was treated with 0.5% carboxymethyl cellulose eye drops 4–6 times a day for 3 months. Follow-up was done at 1 week, 2 weeks, 1 month, and 3 months. On each follow-up visit, the Ocular Surface Disease Index (OSDI) score, tear film breakup time (TBUT), corneal fluorescein staining (CFS) score, and Schirmer test score were noted. At the last follow-up, the abovementioned parameters in both groups were compared.

Study design

Prospective interventional comparative study.

Inclusion criteria

All patients with symptomatic dry eye since last 3 months with an OSDI score of >40, a TBUT score of <10 s (5 mL of fluorescein sodium 2% eye drops was used for each measurement by using a pipette for standardization and the mean value of three readings per eye was taken), positive CFS score (≥grade 1 according to the Van Bijsterveld score), Schirmer test score <10 in 5 min (without topical anesthesia), able to acknowledge and give informed written consent, and able to cooperate with the investigation and treatment plans were taken.

Exclusion criteria

Patients who were unwilling or unable to give consent, refused to accept randomization or follow-up plans, involved in other clinical trial, uncooperative patients, under 18 years of age, pregnant females or expecting to become pregnant during the study, contact lens user, patients with active ocular infection, and patients using other eye drops example anti-glaucoma medications.

Autologous PRP preparation and storage

Autologous PRP was prepared according to the protocol described by Alio et al. in 2012.[15] The patient’s blood was extracted into 10-mL sterile tubes containing 1 mL sodium citrate acting as an anticoagulant. Centrifugation of total blood at optimal condition was done to achieve enrichment of platelets in plasma fraction [Fig. 1]. Next, 3–4 mL of platelet-rich plasma (PRP) was aspirated (one part of PRP was mixed with four parts of BSS to make 20% concentration of autologous PRP (aPRP)) and kept in a sterile amber glass bottles with eye drop applicators under laminar flow cabin. Patients were instructed to wash their hands before the application of eye drop. The bottle in use was given to the patient and instructed to be kept at 2°C–8°C for 1 week, and the remaining bottles were kept in blood bank of our hospital at −20°C.

Figure 1.

Centrifuged blood sample containing PRP

Statistical analysis

Mean and standard deviation of all the parameters were calculated using SPSS Statistics 22, and a comparison of the pre-treatment versus post-treatment parameters in both aPRP group and AT group was done using the paired student’s t test to determine the degree of statistical significance. Comparison of post-treatment parameters in both aPRP group and AT group was done using unpaired student’s t test to determine the statistical significance. P < 0.05 was considered as statistically significant.

Results

The present prospective comparative interventional study was conducted on 121 eyes (61 patients) of symptomatic moderate to severe dry eye. The mean age of the patients in the aPRP group was 52.8 ± 12.8 years, while the mean age of patients in the AT group was 55.5 ± 13.4 years. There was preponderance of female over male in both groups. Demographic data of both the groups is given in Table 1.

Table 1.

Demographic data

	aPRP group	AT group	Total
No. of Patients	31	30	61
Eyes	61	60	121
Male	11	12	23
Female	20	18	38
Mean age (years)	52.8±12.8	55.5±13.4

The common underlying causes of DED were primary lacrimal gland deficiency (age-related dry eye) and dry eye associated with connective tissue disorders. The whole sample completed the follow-up period, and there were no changes in group assignment.

Tables 2 and 3 show the changes in the OSDI score, TBUT, CFS score, and Schirmer test score at 3 months of follow-up in the aPRP group and AT group, respectively. OSDI score reduced and CFS score improved significantly in both aPRP and AT groups, whereas TBUT (s) increased significantly only in the aPRP group. Schirmer test scores also improved in both aPRP and AT groups, but the improvement was statistically nonsignificant in both groups.

Table 2.

Pre- and post-treatment mean scores of parameters in the aPRP group

aPRP group	Mean±SD Pre-treatment	Mean±SD Post-treatment (at 3 months)	Mean difference	P
OSDI score	77.3±17.1	43.9±24.3	33.4	<0.0001
TBUT (s)	2.45±2.26	4.91±2.46	2.46	<0.001
CFS score	2.63±0.54	1.13±0.97	1.5	<0.001
Schirmer test score (mm)	4.14±2.50	4.19±2.48	0.05	0.083

Table 3.

Pre- and post-treatment mean scores of parameters in the AT group

AT group	Mean±SD Pre-treatment	Mean±SD Post-treatment (3 months)	Mean difference	P
OSDI score	74.7±16.1	66.6±19	8.1	<0.001
TBUT (s)	2.91±1.48	3.03±1.5	0.12	0.058
CFS score	2.41±0.59	2.01±0.7	0.4	<0.005
Schirmer test score (mm)	4.26±1.94	4.30±1.9	0.04	0.159

In the aPRP group, the mean OSDI score reduced from 77.3 ± 17.1 to 43.9 ± 24.3 (P < 0.0001), the mean TBUT (s) increased from 2.45 ± 2.26 to 4.91 ± 2.46 (P < 0.001), the mean CFS score reduced from 2.63 ± 0.54 to 1.13 ± 0.97 (P < 0.001), and the mean Schirmer test score (mm) increased from 4.14 ± 2.50 to 4.19 ± 2.48 (P = 0.083) at 3-month follow-up.

In the AT group, the mean OSDI score reduced from 74.7 ± 16.1 to 66.6 ± 19 (P < 0.001), the mean TBUT (s) increased from 2.91 ± 1.48 to 3.03 ± 1.5 (P = 0.058), the mean CFS score reduced from to 2.41 ± 0.59 to 2.01 ± 0.7 (P < 0.005), and the mean Schirmer test score (mm) increased from 4.26 ± 1.91 to 4.30 ± 1.90 (P = 0.159) at 3-month follow-up.

The pre-treatment parameters (OSDI score, TBUT, CFS score, and Schirmer test score) in both groups were comparable (P > 0.05). Table 4 compares the mean values in both groups at 3-month follow-up. The OSDI score reduced in both groups, but the reduction was more in the aPRP group as compared to AT group, and the mean difference (MD: −22.7) was statistically significant (P < 0.0001). Improvement in TBUT and CFS score was significantly more in the aPRP group as compared to that in the AT group (P < 0.001 and P < 0.0001, respectively). There was no significant difference in the mean Schirmer test score between both groups (P = 0.44). Although at last follow-up, the mean Schirmer test score (mm) was more in the AT group (4.30 ± 1.90) as compared to aPRP group (4.19 ± 2.48), the improvement in the mean Schirmer test score was more in the aPRP group (0.05 mm) as compared to the AT group (0.04 mm). Bruising at the site of blood withdrawal was noted in two patients in the aPRP group.

Table 4.

Comparison of various parameters in both groups at the end of 3 months

Parameters	Mean Score (aPRP group)	Mean Score (AT group)	Mean difference	P
OSDI score	43.9±24.3	66.6±19.8	−22.7	<0.0001
TBUT (s)	4.91±2.46	3.03±1.56	1.8	<0.001
CFS score	1.13±0.97	2.01±0.72	−0.92	<0.0001
Schirmer test score (mm)	4.19±2.48	4.30±1.90	−0.11	0.44

Discussion

Blood derivatives such as autologous serum and aPRP are the newer modalities for the treatment of dry eye. Fox et al.[6] first described the benefits of AS for the treatment of dry eyes in patients with Sjogren’s syndrome and later described by Tsubota et al.[7] Blood derivatives have added advantages over artificial tears as being preservative-free and present a greater similarity to the natural healthy tear film in terms of pH, osmolarity, and biomechanical properties.[16] AS contains vitamins and fibronectin, which have epitheliotropic effects and help to maintain ocular surface integrity. However, AS is very poor in growth factors because platelets are eliminated in the process of its production.[17] As a new alternative, aPRP is a hemoderivative product, different from AS, and has been proposed for the treatment of DED.[18]

The theoretical background of using PRP is the supplementation of important tear components that may be lacking in dry eyes and cannot be supplemented by artificial tear substitutes. PRP becomes more effective when presenting higher indexes of growth factors such as epithelial growth factor (EGF), vitamin A, neural growth factor (NGF), insulin type I growth factor,[19] and platelet factor IV.[20] PRP is a preservative-free biological product from the patient’s own blood having a platelet concentration above baseline. The main advantage of PRP over other products is the presence of the platelets and the prolonged release of growth factors that are involved in the wound-healing process of the cornea and conjunctival surface.[21,22] PRP can be stored at −20°C for up to 3 months maintaining constant or slight variations in the concentration of the most important growth factors.[23]

We reported a significant reduction in the mean OSDI score in the aPRP group (P < 0.0001). Similar results were obtained by Alio et al. (2017),[24] Sanchez-Avila et al. (2017),[25] and Merayo-Lloves et al. (2016).[26] In the present study, the OSDI score reduced in both the groups, but the reduction was more in the aPRP group (43.2%) as compared to the AT group (10.8%), with a mean difference of −22.7, which was statistically significant (P < 0.0001). Our results correlated with the results of Celebi et al.,[27] who noted a 55.18% reduction in the OSDI score in AS versus a 19.50% reduction in the preservative-free artificial tears (PFAT) treatment group (P < 0.001). Yılmaz et al.[28] compared autologous serum versus PFAT in patients with dry eyes due to systemic isotretinoin therapy and found that the OSDI score reduced significantly in both groups, but OSDI score reduction was more significant in the AS group as compared to the PFAT group (P < 0.0001). Wang et al. (2020)[29] studied autologous serum eye drops versus artificial tear drops for DED and concluded that the OSDI after AS treatment was lower than that after the AT treatment.

The present study showed a significant improvement in the mean TBUT (s) at 3-month follow-up in the aPRP group (P < 0.001), whereas after AT treatment, the improvement was nonsignificant (P = 0.058). At the final follow-up, the difference between both groups was statistically significant (P < 0.001). In the aPRP group, an improvement of >2 s was seen in 42.6% (26 eyes) of the cases, while the remaining 57.4% (35 eyes) of the cases showed an improvement of 1–2 s. Worsening of TBUT was not seen in any of the patients. Takashi et al. (2005)[9] also noted a significant improvement in the mean TBUT in patients treated with autologous serum eye drop as compared with subjects treated with PFAT after 2 weeks of treatment. Similar results were noted by Celebi et al. (2014),[27] Noda-Tsuruya et al. (2006),[30] Yılmaz (2017),[28] and Wang et al.[29] Alio et al.[31] noted an improvement of >2 s in the TBUT in 46% of the cases after treatment with PRP.

We noted a significant reduction in the CFS score in both aPRP and AT groups (P < 0.001 and P < 0.005, respectively) at the last follow-up. However, the reduction in the CFS score was much lower in the aPRP group as compared to that in the AT group, and this difference between both groups was significant (P < 0.0001). Similar results were obtained in a study done by Takashi Kojima et al. (2005),[9] which showed a significant improvement in the CFS score in the patients assigned to autologous serum eye drops compared with subjects assigned to PFAT after 2 weeks of treatment. Alio et al. (2017)[24] and Natanael et al. (2019)[32] also showed that after the use of autologous PRP in severe dry eye, the Oxford scale score of CFS decreased significantly (P < 0.05). In contrast to the present study, Wang et al. (2020)[29] and Noda-Tsuruya et al. (2006)[30] noted no significant difference in the CFS scores between patients using autologous serum eye drops and patients using artificial tears.

In our study, the mean Schirmer test score at the final follow-up increased in both groups, but the increment was nonsignificant as compared to the pre-treatment value. The mean difference between both groups at the final follow-up was also statistically nonsignificant (P = 0.44). Noda-Tsuruya et al. (2006)[30] and Wang et al. (2020)[29] compared autologous serum with artificial tears for dry eyes and obtained similar results. In contrast to the present study, Celebi et al. (2014),[27] Jirsova et al.,[33] Hussain,[17] and García-Conca et al. (2018)[34] reported a significant increase in the Schirmer test score with the use of autologous serum/PRP as compared to artificial tear in patients of DED.

Conclusion

Autologous PRP treatment provides a greater improvement in signs and symptoms of DED patients as compared to AT treatment. It is a safe therapy without any serious adverse effects, with the added benefit of being preservative free. aPRP can be given safely up to 10–12 weeks with a significant improvement in moderate to severe DED. Thus, we conclude that aPRP is safe and more effective than AT in treating patients with symptomatic moderate to severe DED.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.