Persistent keratitis, corneal ulcers, keratoconjunctivitis sicca, chronic exposure keratopathy, corneal neovascularization, and neurotrophic disease can be especially difficult to treat. Steroids, antibiotics, cyclosporin, lifitegrast and amniotic membranes may fail in some cases. Insurance may not cover medications deemed medically necessary. For some, using cyclosporin, loteprednol and artificial tears hourly is prohibitively expensive.  In these cases, I am using autologous serum more often. Autologous serum and Platelet Rich Plasma have both been reported to be beneficial in the treatment of ocular surface disease. Homologous sources, including allogeneic serum obtained from healthy donors, and umbilical cord blood serum collected at the time of delivery are efficient alternatives when autologous serum therapy is contraindicated or not appropriate.(1) Advantages to using autologous serums include natural healing factors, and freedom from HIV, hepatitis, and other transmissible diseases.(2)

Autologous serum, while a lubricant, also facilitates recovery of damaged epithelium by delivering cytokines, vitamin A, epidermal growth factor, and fibronectin. Serum eye drops have been effectively used for the treatment of ocular surface diseases, severe dry eye, persistent epithelial defects, neurotropic keratopathy, and recurrent erosions.(3) Topical application of serum eye drops has been reported to accelerate healing of persistent ocular surface defects. Azari, et al, reported autologous serum was beneficial in patients with Graft Versus Host Disease who suffer from dry eyes.(4) It has been also reported as beneficial for treatment of filamentary keratitis.(5)

Cho, et al, compared autologous serum concentrations in the eyes with Sjögren syndrome and persistent epithelial defects.(6) They found 100% concentration most effective in decreasing symptoms, corneal epitheliopathy, and wound closure. In the eyes with keratoconjunctivitis, Non-Sjögren type, 100%, and 50% concentrations had similar effects in decreasing symptoms and corneal epitheliopathy. 100% concentrations are difficult to filter in by the pharmacy, however. 

Turkoglu, et al, investigated efficacy of autologous serum eye drops compared to amniotic membrane transplantation for treatment of neurotrophic corneal ulcers.(7) Study targets were epithelial healing time and best corrected visual acuity before and after treatments. Both autologous serum eye drops and amniotic membrane transplantation are effective for eyes with neurotrophic corneal ulcers but they reported multilayered amniotic membrane transplantation is more effective than autologous serum in their cases of deep corneal ulcers with post-herpetic neurotrophic keratitis.

Semeraro, et al, evaluated changes following autologous serum drops in Sjögren’s syndrome-related dry eyes using confocal microscopy.(8) Twenty-four patients with Sjögren’s syndrome using autologous serum drops (12 patients) and artificial tears only (12 patients) were compared to 24 healthy volunteers. Ocular Surface Disease Index (OSDI), central corneal thickness, tear film, break-up time, corneal and conjunctival staining, Schirmer’s test and corneal confocal microscopy were investigated. Improvements in the treatment groups were reported in tear production, tear film stability, corneal staining, inflammation using biomicroscopy. Central corneal thickness, Langerhans cells, activated keratocytes, intermediate epithelial cell density, nerve tortuosity, number of sub-basal nerve branches, and number of bead-like formations improved after treatment as measured with confocal microscopy.

Mahelkova, et al, used corneal confocal microscopy to identify the possible effects of a three-month treatment with autologous serum.(9) They reported a significant decrease in corneal fluorescein staining after the three-month autologous serum treatment. Basal epithelial cell density decreased significantly, while the density of superficial epithelial cells and number of Langerhans cells or activated keratocytes was not significantly different after treatment. 

Use of autologous serum following elective vision correction procedure has been studied as well. Hondur, et al, evaluated the effect of autologous serum on the rate of epithelial healing after laser epithelial keratectomy (LASEK) for correction of myopia.(10) The mean time to epithelial healing was about 1 day shorter in the eyes receiving autologous serum than the eyes receiving conventional treatment. No significant difference was noted in the incidents of haze. Akcram, et al, reported the mean duration for epithelial healing following PRK was about one day shorter in the eyes receiving autologous serum compared to the eyes receiving conventional treatment.(11)

Platelet-rich plasma (PRP) contains more concentrated platelets than whole blood, and is an alternative to autologous serum.  PRP is defined as a portion of the plasma fraction of autologous blood having a platelet concentration above baseline. PRP has more concentrated platelets than normal plasma (approximately 150–400 × 10 /L). In such conditions, PRP contains a high level of platelets, but also the full complement of clotting factors.(1) Platelets are great sources of platelet-derived growth factors (PDGFs), transforming growth factors (TGFs), vascular endothelial growth factor, and epithelial growth factor.

Platelets are especially beneficial to the wound-healing process. They rapidly travel to the wound site, adhere to the damaged tissue, and initiate a healing reaction. This results in the release of cytokines and growth factors. Improved outcomes with PRP eye drops compared to autologous serum eye drops in patients with persistent epithelial defect after infectious keratitis have been reported.(1,12) Plasma rich in growth factors fibrin membrane (mPRGF) (used as a graft or dressing) accelerates tissue regeneration after ocular surface surgery thus minimizing inflammation and fibrosis.(13)

Sánchez-Avila, et al, evaluated using plasma rich in growth factors (PRGF) drops in patients with glaucoma with secondary ocular surface disorders.(14) A small case-series study of six patients (eight eyes) diagnosed with glaucoma, S/P surgical (nonpenetrating deep sclerectomy and/or trabeculectomy) and using hypotensive eye drops to control intraocular pressure, and who developed secondary ocular surface disease unresponsive to conventional treatments were included. Patients were treated with PRGF eye drops four times a day. A statistically significant reduction in OSDI scale (50.6%), symptom severity (42.0%), and a 41.8% improvement in BCVA were observed (p<0.05).

Alio, et al, evaluated the use of autologous platelet-rich plasma drops as monotherapy for the treatment of moderate to severe cases of dry eye disease in 368 patients.(15) Improvement of subjective symptoms, fluorescein staining, and corrected distance visual acuity was evaluated. After 6 weeks of monotherapy treatment with autologous PRP, dry eye symptoms improved in 322 (87.5%) cases. A decrease of fluorescein staining was observed in 280 (76.1%) patients. 28.8% patients improved at least 1 line of best corrected visual acuity. The scores in the Ocular Surface Disease Index and the Oxford scale of corneal fluorescein staining decreased statistically after the treatment (p < 0.05).

Compounding Serum

My office uses a two-page handout that includes the written prescription for the blood draw, desired usage instructions for the drops for the compounding pharmacy, maps and contact information for the lab and compounding pharmacy. This facilitates required visits and reduces confusion. I have found this to be an extremely easy way to instruct patients in obtaining their serum.

Both AS and PRP are created from blood drawn from the patient, typically by a local laboratory. This blood draw is typically reimbursed by insurance, but you need to check with the lab. The blood is marked to ensure correct tracking, and transported to the compounding pharmacy. At that point, the blood may be used to make AS or PRP. Note that your compounding pharmacy may restrict blood draws to their preferred lab so be sure to ask what labs they suggest.

Autologous serum is created from whole blood at room temperature. The samples are allowed to set for 2 hours or so to allow it to clot. The blood is centrifuged at 5,600 rpm for approximately 10 minutes. The serum is filtered before mixing with saline to remove fibrin strands, which are believed to lessen the effect of ASEDs. Each 8.5cc tube of blood yields approximately 4cc of serum (24cc total) at 20%.(16) Others use a 50% serum dilution.  Concentrations above 50% are difficult to filter so my compounding pharmacy won’t make greater than 50% AS. The amount and cost of the AS vary with the amount of blood drawn. Drinking water prior to the blood draw is recommended. 

PRP is created using anticoagulant, which is then gently agitated to mix the anticoagulant thoroughly with the whole blood. The mixture is then centrifuged for 10 minutes at 800 rpm. After centrifugation, the upper fraction of each sample is PRP. Plasma must be carefully separated in a sterile manner under clean bench conditions. According to my pharmacy, this requires special vials that labs do not normally use, and this makes them more expensive. The PRP is then transferred to a sterile bottle and refrigerated or frozen until used. 

There is actually a YouTube video on how to make serum tears at home.  I obviously do not suggest this, but bring it up so readers are aware if their patients ask about buying the required equipment on Amazon. 

Contact your nearest compounding pharmacy to determine if they can perform the necessary procedures for serum tears. They may not be able to make them, or they may be able to create autologous serum but not PRP. We have more than 10 compounding pharmacies in my metro area, but only one can make them. Currently, they only make autologous serum, not PRP. Ask how they will instruct the patient to keep their bottles until use (frozen or refrigerated), the size of the bottles, and the shelf life of a bottle once opened.  Tsubota, et al, reported that the concentration of growth factors, vitamin A, and fibronectin in 100% and 20% serum concentrations, diluted with NaCl and stored at 4°C remained unchanged for 1 month, and when stored at −20°C, were unchanged for at least 3 months.(17) When stored at 4°C, protein concentrations decrease significantly in just weeks. Thus, it is suggested patients freeze unused serum vials to preserve the epitheliotropic factors.(18) Ensure you tell your patient the same information given to them by the compounding pharmacy to reduce confusion.  

Ordering of AS drops in our local pharmacy have become so common that we are now required to call for appointments to ensure they can accommodate all orders on a given day. They currently schedule 4 patients (orders) per day because that is all they can produce in that time. The patient’s appointment times are now added to our two pages of paperwork. 

1. Giannaccare G, Versura P, Buzzi M, Primavera L, Pellegrini M, Campos EC. Blood-derived eye drops for the treatment of corneal and ocular surface diseases. Transfus Apher Sci. 2017 Aug;56(4):595-604. doi: 10.1016/j.transci.2017.07.023.

2. Tzu En Wu, Chiung Ju Chen, Chao-Chien Hu, and Cheng-Kuo Cheng. Easy-to-prepare autologous platelet-rich plasma in the treatment of refractory corneal ulcers. Taiwan J Ophthalmol. 2015 Jul-Sep; 5(3): 132–135. doi: 10.1016/j.tjo.2014.09.001.

3. Jun Hun Lee, Myung Jun Kim, Sang Won Ha, and Hong Kyun Kim. Autologous Platelet-rich Plasma Eye Drops in the Treatment of Recurrent Corneal Erosions. Korean J Ophthalmol. 2016 Apr; 30(2): 101–107. doi: 10.3341/kjo.2016.30.2.101

4. Azari AA; Karadag R; Kanavi MR; Nehls S; Barney N; Kim K; Longo W; Hematti P; Juckett M. Safety and efficacy of autologous serum eye drop for treatment of dry eyes in graft-versus-host disease.  Cutan Ocul Toxicol.  2017; 36(2):152-156.

5. Read SP; Rodriguez M; Dubovy S; Karp CL; Galor A. Treatment of Refractory Filamentary Keratitis With Autologous Serum Tears. Eye Contact Lens. 2017; 43(5):e16-e18.

6. Cho YK; Huang W; Kim GY; Lim BS. Comparison of autologous serum eye drops with different diluents. Curr Eye Res.  2013; 38(1):9-17.

7. Turkoglu E1, Celik E, Alagoz G. A comparison of the efficacy of autologous serum eye drops with amniotic membrane transplantation in neurotrophic keratitis. Semin Ophthalmol.  2014; 29(3):119-26.

8. Semeraro F; Forbice E; Nascimbeni G; Taglietti M; Romano V; Guerra G; Costagliola C.  Effect of Autologous Serum Eye Drops in Patients with Sjögren Syndrome-related Dry Eye: Clinical and In Vivo Confocal Microscopy Evaluation of the Ocular Surface. In Vivo. 2016; 30(6):931-938.

9. Mahelkova G; Jirsova K; Seidler Stangova P; Palos M; Vesela V; Fales I; Jiraskova N; Dotrelova D. Using corneal confocal microscopy to track changes in the corneal layers of dry eye patients after autologous serum treatment. Clin Exp Optom. 2017; 100(3):243-249.

10. Hondur AM; Akcam HT; Karaca EE; Yazici Eroglu H; Aydin B. Autologous Serum Eye Drops Accelerate Epithelial Healing After LASEK. Curr Eye Res. 2016; 41(1):15-9.

11. Akcam HT, Unlu M, Karaca EE, Yazici H, Aydin B, Hondur AM. Autologous serum eye-drops and enhanced epithelial healing time after photorefractive keratectomy. Clin Exp Optom. 2018 Jan;101(1):34-37.

12. Anitua E, de la Fuente M, Muruzabal F, Riestra A, Merayo-Lloves J, Orive G. Plasma rich in growth factors (PRGF) eye drops stimulate scarless regeneration compared to autologous serum in the ocular surface stromal fibroblasts. Exp Eye Res. 2015; 135:118-26

13. Sanchez-Avila RM, Merayo-Lloves J, Riestra AC, Berisa S, Lisa C, Sánchez JA, Muruzabal F, Orive G, Anitua E. Plasma rich in growth factors membrane as coadjuvant treatment in the surgery of ocular surface disorders. Medicine (Baltimore). 2018 Apr;97(17):e0242.

14. Sánchez-Avila RM, Merayo-Lloves J, Fernández ML, Rodríguez-Gutiérrez LA, Rodríguez-Calvo PP, Fernández-Vega Cueto A, Muruzabal F, Orive G, Anitua E. Plasma rich in growth factors eye drops to treat secondary ocular surface disorders in patients with glaucoma.   Int Med Case Rep J. 2018 May 1;11:97-103.

15. Alio JL, Rodriguez AE, Ferreira-Oliveira R, Wróbel-Dudzińska, Abdelghany AA  Treatment of Dry Eye Disease with Autologous Platelet-Rich Plasma: A Prospective, Interventional, Non-Randomized Study. Ophthalmol Ther. 2017 Dec;6(2):285-293.

16. R Mangan, and S Lehman. How (and Why) to Make Autologous Serum. Review of Optometry.  March 15, 2012.  Access 6/1/2018.

17. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjögren’s syndrome. Br J Ophthalmol 1999;83:390–5.

18. Sitaramamma T, Shivaji S, Rao GN. Effect of storage on protein concentration of tear samples. Curr Eye Res 1998;17:1027–35.