Autologous and Allogenic Serum Tears
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Introduction
In the U.S. Dry eye disease (DED) affects 16.4 million people, roughly 6.8% of the entire population [Farrand 2017].[1] It is likely that 6 million more Americans (2.5%) also suffer from symptoms of DED without a formal diagnosis, bringing the overall burden of DED to nearly 10% of the U.S. population [O'Neil EC 2019].[2] Globally, prevalence is even higher: 11% of the world’s population suffer from DED [Pappas 2021].[3] DED makes up a large proportion of Ocular surface disease (OSD), which includes but is not limited to inadequate lubrication of the ocular surface.
DED is a chronic disease that requires multiple treatment modalities. As of yet, there is no gold standard for DED treatment [Dogru 2011].[4] Current treatment includes environmental and behavioral modification, as well as medical and surgical therapies. Medical therapy often takes the form of topical ointments and drops/artificial tears. Surgical procedures include punctal plugs and punctual cautery. There are several formulations of drops including preservative-free artificial tears and serum eye drops (SEDs), which include autologous serum tears (AS) and allogeneic serum tears (ALS). Autologous serum tears were first described in 1975 [Ralph RA 1975].[5] Since then, their use has become widespread. Because serum contains many components shared by natural tears, it was theorized that serum eye drops would improve dry eye by supplementing endogenous components: restoring the ocular surface. These components include vitamins, structural proteins, enzymes and growth factors. Importantly, serum and tears have similar albumin content and osmolality. These and other properties make tears derived from serum an attractive option for patients with severe DED as well as other OSD types, especially those who have not improved with first-line therapy. Further--because they are preservative free--SEDs can be used for prolonged periods. Finally, they have a limited side-effect profile as they are composed of endogenous components.
Background
AS tears were first reported in 1975 for the treatment of tear deficiency in a cohort of patients with varying OSD. AS tears successfully improved OSD related to several etiologies: systemic disease with ocular involvement, ocular surface pathology and post-operative patients [Ralph RA, 1975].[5] Patients reported “almost unanimous satisfaction”. Since this study, AS have been used for several types of OSD including severe DED, Sjogrens, ocular graft versus host disease, Steven Johnson syndrome/toxic epidermal necrolysis, SLE, uveitis, chemical burns, herpes keratitis, persistent corneal epithelial defect, and more [Ripa 2020].[6]
DED is the most common of the aforementioned diseases for which serum tears have been used to treat successfully. Signs and symptoms include visual changes, irritation, foreign body sensation and redness. Patients with intact sensation may experience symptoms of dry eye disease, leading to better management in some cases. On the other hand, patients with impaired sensation may have more severe disease. For patients with severe DED, AS can restore the integrity of the tear film, and does so with endogenous tissue components. Despite sharing endogenous origins, there are substantial differences between serum and tears regarding their proteins and growth factors. Also, it is important to consider that donated serum can be used to make serum for the donor, or for another recipient. While Autologous Serum (AS) drops are derived from a patient’s own serum, serum drops can also be obtained from a donor (ALS). This can be advantageous in those patients who are poor candidates for serum donation. At present no preparation of serum tears has FDA approval for treatment of DED/OSD. Still, data from multiple studies has shown their efficacy for signs and symptoms of DED and OSD [1. M. beylerian, m Lazaro et al autologus serum tears: long-term treatment in the dry eye syndrome; 2. 31561880].[7] Unfortunately, there are few randomized controlled trials (RCT) testing the efficacy of AS tears for patients with DED and other OSD. It is likely that future RCTs of serum tears will result in increased access and lowered cost for serum tears.
Basic Concepts
Tear Film
The tear film is the most superficial layer of the eye, and the first component of the visual pathway. Tears are produced in lacrimal glands and drained via the lacrimal drainage system. They are composed of an aqueous, mucin and lipid component. The tear film is essential for both vision and ocular health: it lubricates the surface of the eye and allows a smooth refractive surface for good vision. Normal tears contain vital proteins and growth factors that promote ocular health. The total protein content of tears is 7.51%, which is roughly 10% lower than serum’s protein content [Higuchi 2018].[8] Major tear proteins include lysozyme, lactoferrin and albumin. Lysozyme protects against ocular surface infection. Lactoferrin transports iron into the cornea and is integral to protecting the cornea from oxidative stress. Importantly, these proteins are not known to be found in serum, the Major proteins therein include albumin and serum IgG.
Pathophysiology of DED/OSD
DED is an ocular surface disease of multifactorial etiology. DED has been recently re-defined as a disease “where loss of homeostasis of the tear film is the central pathophysiological concept” [Craig 2017].[9] There are two major types of tear film dysfunction: evaporative and aqueous deficiency. These etiologies are not mutually exclusive, and in many cases both disease etiologies are present. Aqueous deficiency alone accounts for 10% of disease burden, while mixed aqueous and hyper evaporative-deficient accounts for more than 80% of DED cases [messmer 2015].[10]
Hyperevaporative vs Aqueous-deficient tear film dysfunction:
Evaporative tear film dysfunction is involved in most cases of DED. The leading cause of evaporative eye disease is Meibomian gland dysfunction. Other causes include blinking abnormalities, contact lens use and topical drops with preservatives [Chan 2019].[11] Current treatments for meibomian gland dysfunction begin with less-invasive treatment techniques--including warm compresses--escalating to the more invasive techniques such as corticosteroids or cyclosporine A [Messemer 2015].[10] Aqueous tear film dysfunction typically relates to lacrimal gland function. Autoimmune disease may play a role here as well, as in Sjogren’s disease. In aqueous deficient DED, glands may be obstructed, deficient or suffering from drug side effects [Chan 2019].[11] Some experts argue that lid hygiene is more helpful in hyperevaporative dry eye, and plugs (silicon and collagen) can relieve signs and symptoms of hyposecretory DED, though they are useful in further cases, especially if drop application is problematic (elderly or very young patients).
DED/OSD Risk Factors: Women and older adults are at higher risk of DED, as well as patients with systemic disease, neurological deficits (e.g., decreased corneal sensation) nutritional deficiency (e.g., vitamin A deficiency), contact lens wear, as well as some medications. Other common factors contributing to DED include UV radiation and oxidative stress, systemic inflammation, neurological damage and surgery.
Role of inflammation in DED: Several publications suggest that DED is an inflammatory disease with a mechanism similar to autoimmune diseases. These studies suggest a repetitive cycle of insult and inflammation to the ocular surface. For example, an environmental antigen will trigger release of inflammatory cytokines and other proteins which will activate T-cells on the ocular surface and lacrimal gland [Messmer 2015, Stern 2013, Stevenson 2012].[10][12] [13] Additionally, oxidative stress has been shown to play a role in DED as well. Studies have shown that imbalances between reactive oxygen species and protective enzymes may be associated with oxidative damage and inflammation on the ocular surface [Seen 2017].[14]
Mechanism of Serum Tears
Most artificial tears contain 3 components: a preservative, cellulose and polyethylene glycol. Cellulose provides viscosity, and polyethylene glycol promotes surface coverage. These formulations are available in drop and ointment forms to suit patient preference. While these formulations serve to support the health of the ocular surface, they lack the growth factors, platelets and proteins that are found in serum and the healthy tear film. Artificial tears made from serum do contain these components, and it is thought that for this reason they are an effective treatment for OSD refractory to artificial tears and topical medications.
Serum tears are a blood-derived biomaterial and are therefore high in platelets and platelet-derived growth factors [Tseng, 2015].[15] Specifically, serum contains EGF, NNGF, TGF-alpha, KGF, HGF, IGF-1 and VEGF [Chan 2019].[11] Further, serum contains vitamins A and E and fibronectin [Marks 2015].[16] Together they serve to inhibit apoptosis and improve cell growth and migration [Blair 2009].[17] Experts believe that the combination of growth factors facilitates cell expansion and differentiation and differentiation in Vivo [Tseng, 2015].[15]
By providing actual components of healthy tear substrate, serum tears target the mechanism underlying the patient's OSD (DED, SJS, Uveitis etc.). For example, Sjogren’s disease is often accompanied by damage to the corneal epithelium. The cornea is composed of keratocytes: cells whose growth is stimulated by growth factors that are contained in platelet alpha granules. AS tears—containing platelets and alpha granules—have been shown to improve corneal pathology secondary to Sjogren’s disease [TsubotaK, 1999].[18] Importantly, studies have shown that the components that promote healing—growth factors EGF and TGF-B—were preserved when stored in a freezer for three months at -20 degrees C. Another study showing that serum tears actually reverse ocular pathology, demonstrates that serum tears promote corneal nerve regeneration [Aggarwal 2016].[19] The authors of this study reported restoration of corneal nerve topography, which correlated with patient’s self-reports of photoallodynia relief.
Finally, serum has a high Albumin content, a protein known to have antioxidant properties. Specifically, Albumin’s free thiol group on Cyst34 allows it to easily interact and neutralize free oxygen and nitrogen radicals [Belinskaia, 2021].[20] This may offer protection to the ocular surface regarding oxidative damage.
Patient Selection
Indications
Serum tears are typically used for patients with OSD who have not shown improvement with artificial tears, and other conservative/topical treatments. Previous reports describe serum tears used for autoimmune disease, trauma and even perioperatively [Purushothama 2021, Toda 2018, Ralph RA, 1975].[21][5] Most patients make good candidates for donation of their own serum for AS tear manufacturing, and almost all patients are good candidates for use of serum tears: autologous or allogeneic. A healthy serum donor should meet the following criteria: good venous access, adequate Hb level, prior evaluation and donation of 500ml of whole blood, ability to store tears at -18 degrees Celsius, and ability to place the vials in use at 4 Celsius [VanderMeer 2021].[22]
Of note, patients who have significant ongoing inflammatory pathology have demonstrated varying outcomes with autologous serum tears. For example, one study of patients using serum tears in patients with active vs inactive systemic inflammatory disease showed increased inflammatory markers and poorer clinical responses to treatment [Chen, 2017].[23]
Contraindications
AS tear drops are contraindicated in patients who cannot tolerate repeated blood draws, but these patients should still tolerate allogeneic tears well. Other conditions that complicate serum donation include poor venous access, low Hb level, fear of needles, advanced patient age and limited mobility. Many of these factors disproportionately affect the elderly, as does DED/OSD [VanderMeer 2021].[22] There has been apprehension about the use of autologous serum tears in patients with communicable blood/serum diseases [Citation]. Fortunately, these patients should also make good candidates for allogeneic serum tears. It may be safe to use autologous serum tears in patients with communicable diseases however [29784164].[24] Still, it is prudent that caution be taken in patients with such diseases to prevent any possibility of contamination/disease transmission. Finally, there is a risk of ocular infection if AS are stored improperly. Complications are rare, especially when compared to alternative therapies cyclosporine and lifitegrast.
Barriers to use of Serum Tears
The largest barrier to serum tears at this time is probably economic cost. One author wrote treatment ranges from $678 to $1267 [Cui 2020].[25] Still, despite the large cost, they are comparable to some of the artificial tears with FDA approval today. Unfortunately, at this time serum tears are not FDA approved, and therefore not covered by most insurance policies [Cui 2021. This constitutes a significant barrier for lower-income patients.
There is hope for patients with OSD who are poor donor candidates for serum donation. Specifically, there are the studies that suggest allogeneic drops are as effective as autologous drops. Specifically, one study showed no difference in ocular surface disease index between patients treated with autologous and allogeneic serum drops. This study also showed no difference in tear break up time between the two groups [Van der meer, 2021].[22] This suggests that inability to donate serum does not mean that a patient cannot benefit from serum tears.
Advantages
The inclusion of endogenous components--and the lack of artificial ones—are two of the most salient advantages of serum tears. Serum tears therefore lack the side effect profile accompanying most artificial tears containing preservatives. Further, the endogenous components give serum tears the ability to promote healing of the ocular surface, as opposed to only providing symptomatic relief. Another important advantage, however, is their economy of production. One study reports that a single blood donation provides a year’s worth of AS tears in Australia [Marks 2015].[16] This ability to produce tears is becoming competitive with commercially available options (e.g., Restasis) in the U.S. and elsewhere.
Formulations
There are two popular formulations of serum tear derivatives: autologous serum and platelet rich plasma. To obtain serum for tear manufacture, a patient’s blood will be drawn, and centrifuged to separate blood into plasma, RBCs and WBC components. The serum component of blood will be extracted and refrigerated. Autologous serum production allows blood clotting in this process, which does allow inflammatory cytokines from monocytes and leukocytes. The solution may be diluted with saline 20-50%, which will reduce cytokine load [Ribeiro, 2018].[26] Platelet rich plasma does contain platelets, with high concentrations for growth and plasma factors. It is not diluted prior to use, and it is believed that intact/inactivated platelet introduction to the ocular surface will promote ocular surface healing.
Effects and Safety
Side effects of artificial tears are many and vary with the preparation/concentration and amount of preservatives used in the formula. Compared to artificial tears, there are several benefits, and few side effects associated with serum tears. Provided that they are produced and stored according to protocol, the safety concerns associated with Autologous serum tears are minimal.
Studies and Trials
Current data on autologous serum tears is based on relatively small, single center reviews. Therefore, multiple authors state the need for RCTs to determine the efficacy of serum tears [Pan 2013, Shtein 2020, Cui 2021].[27] [28][25] While the field is expanding, there are still several remarkable studies of serum tears. Some have looked at serum tear efficacy, and others have compared autologous vs allogeneic tears, as well as the long-term effects of serum tears on symptom management and tear production.
Postoperative dry eye
Dry eye is a common postoperative outcome after Lasik surgery. One study determined a decrease in tear break up time in patients during postop period following Lasik surgery [Toda,2018].[21] One study of serum tear efficacy demonstrates an increase in tear-break up time of 2 seconds [Pan,2017].[27] This may make serum tears helpful in treating or even preventing postoperative dry eye.
Tear production
In at least one study using Shirmer’s and tear break up time, investigators found that patient use of AS tears for one month did result in improved tear production and flow stability. Further AS tear use was associated with an increase in goblet cell density [Castillo, 2021].[29]
Reduction in OSD severity despite systemic inflammatory disease
One observational study examining use of autologous serum tears to improve Ocular disease surface index (ODSI) scores in patients with systemic and ocular inflammatory disease found a decrease in both groups. Though the group without systemic disease showed greater improvement, both groups still benefited from AS tears [Ripa, 2020].[6]
Superficial Punctate Keratitis and Persistent Epithelial Defect
One study examining the use of autologous serum for the treatment of ocular surface disease at a Swedish tertiary center found improvement in patients with Superficial punctate keratitis and persistent epithelial defect (PED), with complete or partial healing in nearly all eyes that were not lost to follow up in patients with SPK [Von Hofsten, 2016][30]
Autologous vs Allogeneic tears
Autologous and allogeneic drops have comparable efficacy and tolerability for use in patients with severe dry eye disease. This makes the patient's ability to donate their own serum less of the barrier than it has been previously. Hopefully this and future studies lead to production of “off-shelf” allogeneic tears. [Van der Meer PF, 2021].[22] Outcomes of Long-term treatment with serum tears have been promising as well. A single center study in France showed patients treated with AS with a mean follow up time of 10 months had high clinical efficacy, no infections and high satisfaction [Beylerian 2018].[7]
Complications
The most feared complication from serum tears is infection. This has been known to occur in few studies. At this time the risk of infection is low provided patients freeze and refrigerate their artificial tears according to protocol.
Summary
First introduced in 1975, serum tears currently represent an effective second-line treatment for DED, and ocular surface disease more generally. While these formulations serve to support the health of the ocular surface, they lack the growth factors, platelets and proteins that are found in serum and the healthy tear film. Artificial tears made from serum do contain these components, and it is thought that for this reason they are an effective treatment for OSD refractory to artificial tears and topical medications. Future randomized-controlled trials will likely solidify the position of serum tears in the treatment of ocular surface disease, hopefully leading to FDA approval.
References
- ↑ Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. Prevalence of Diagnosed Dry Eye Disease in the United States Among Adults Aged 18 Years and Older. Am J Ophthalmol. 2017 Oct;182:90-98. doi: 10.1016/j.ajo.2017.06.033. Epub 2017 Jul 10. PMID: 28705660.
- ↑ O'Neil EC, Henderson M, Massaro-Giordano M, Bunya VY. Advances in dry eye disease treatment. Curr Opin Ophthalmol. 2019;30(3):166-178. doi:10.1097/ICU.0000000000000569
- ↑ Papas EB. The global prevalence of dry eye disease: A Bayesian view. Ophthalmic Physiol Opt. 2021 Nov;41(6):1254-1266. doi: 10.1111/opo.12888. Epub 2021 Sep 21. PMID: 34545606.
- ↑ Dogru M., Tsubota K. Pharmacotherapy of dry eye. Expert Opinion on Pharmacotherapy. 2011;12(3):325–334. doi: 10.1517/14656566.2010.518612. [PubMed]
- ↑ 5.0 5.1 5.2 Ralph RA, Doane MG, Dohlman CH. Clinical experience with a mobile ocular perfusion pump. Arch Ophthalmol. 1975;93(10):1039–1043.
- ↑ 6.0 6.1 Ripa M, Jabbehdari S, Yazdanpanah G, Lukacs E, Karcher B, Iqbal O, Bouchard C. The Role of Multisystem Disease in Composition of Autologous Serum tears and ocular surface symptom improvement. Ocul Surf. 2020 Jul;18(3):499-504. doi: 10.1016/j.jtos.2020.02.011. Epub 2020 Feb 29
- ↑ 7.0 7.1 Beylerian M, Lazaro M, Magalon J, Veran J, Darque A, Grimaud F, Stolowy N, Beylerian H, Sabatier F, Hoffart L. Collyres de sérum autologue : traitement à long-terme dans le syndrome sec oculaire [Autologous serum tears: Long-term treatment in dry eye syndrome]. J Fr Ophtalmol. 2018 Mar;41
- ↑ Higuchi A, Takahashi K, Hirashima M, Kawakita T, Tsubota K. Selenoprotein P controls oxidative stress in cornea. PLoS One. 2010;5:e9911. © 2010 Higuchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.
- ↑ Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, Liu Z, Nelson JD, Nichols JJ, Tsubota K, Stapleton F. TFOS DEWS II Definition and Classification Report. Ocul Surf. 2017 Jul;15(3):276-283. doi: 10.1016/j.jtos.2017.05.008. Epub 2017 Jul 20. PMID: 28736335.
- ↑ 10.0 10.1 10.2 Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 2015 Jan 30;112(5):71-81; quiz 82. doi: 10.3238/arztebl.2015.0071. PMID: 25686388; PMCID: PMC4335585.
- ↑ 11.0 11.1 11.2 Chan TCY, Chow SSW, Wan KHN, Yuen HKL. Update on the association between dry eye disease and meibomian gland dysfunction. Hong Kong Med J. 2019 Feb;25(1):38-47. doi: 10.12809/hkmj187331. Epub 2019 Jan 31. PMID: 30713149.
- ↑ Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32:19–41.
- ↑ Stevenson W, Chauhan SK, Dana R. Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol. 2012;130:90–100.
- ↑ Seen S, Tong L. Dry eye disease and oxidative stress. Acta Ophthalmol. 2018 Jun;96(4):e412-e420. doi: 10.1111/aos.13526. Epub 2017 Aug 21. PMID: 28834388.
- ↑ 15.0 15.1 Tseng CL, Seghatchian J, Burnouf T. Animal models to assess the therapeutic efficacy of human serum and serum-converted platelet lysates for dry eye syndrome: Seeing is believing. Transfus Apher Sci. 2015 Aug;53(1):95-8. doi: 10.1016/j.transci.2015.05.016. Epub 2015 Jun 9. PMID: 26096279.
- ↑ 16.0 16.1 Marks DC, Fisher J, Mondy P, Segatchian J, Dennington PM. Serum eye drop preparation in Australia: Current manufacturing practice. Transfus Apher Sci. 2015 Aug;53(1):92-4. doi: 10.1016/j.transci.2015.05.015. Epub 2015 Jun 9. PMID: 26123029.
- ↑ Blair P., Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Reviews. 2009;23(4):177–189. doi: 10.1016/j.blre.2009.04.001. [PMC free article]
- ↑ Tsubota K, Higuchi A (2000) Serum application for the treatment of ocular surface disorders. Int Ophthalmol Clin 40: 113–122.
- ↑ Aggarwal S, Kheirkhah A, Cavalcanti BM, Cruzat A, Colon C, Brown E, Borsook D, Prüss H, Hamrah P. Autologous Serum Tears for Treatment of Photoallodynia in Patients with Corneal Neuropathy: Efficacy and Evaluation with In Vivo Confocal Microscopy. Ocul Surf. 2015 Jul;13(3):250-62. doi: 10.1016/j.jtos.2015.01.005. Epub 2015 Feb 20. PMID: 26045233; PMCID: PMC4499014.
- ↑ Belinskaia DA, Voronina PA, Shmurak VI, Jenkins RO, Goncharov NV. Serum Albumin in Health and Disease: Esterase, Antioxidant, Transporting and Signaling Properties. Int J Mol Sci. 2021 Sep 25;22(19):10318. doi: 10.3390/ijms221910318. PMID: 34638659; PMCID: PMC8508759.
- ↑ 21.0 21.1 Title: Toda I. Dry Eye After LASIK. Invest Ophthalmol Vis Sci. 2018 Nov 1;59(14):DES109-DES115. doi: 10.1167/iovs.17-23538. PMID: 30481814.
- ↑ 22.0 22.1 22.2 22.3 van der Meer PF, Verbakel SK, Honohan Á, Lorinser J, Thurlings RM, Jacobs JFM, de Korte D, Eggink CA. Allogeneic and autologous serum eye drops: a pilot double-blind randomized crossover trial. Acta Ophthalmol. 2021 Dec;99(8):837-842. doi: 10.1111/aos.14788. Epub 2021 Feb 15. PMID: 33590715.
- ↑ Ma IH, Chen LW, Tu WH, Lu CJ, Huang CJ, Chen WL. Serum components and clinical efficacies of autologous serum eye drops in dry eye patients with active and inactive Sjogren syndrome. Taiwan J Ophthalmol. 2017 Oct-Dec;7(4):213-220. doi: 10.4103/tjo.tjo_102_17. PMID: 29296554; PMCID: PMC5747232.
- ↑ Marchand, M., Harissi-Dagher, M., Germain, M., Thompson, P., & Robert, M. C. (2018). Serum drops for ocular surface disease: national survey of Canadian cornea specialists. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie, 53(3), 266–271. https://doi.org/10.1016/j.jcjo.2017.09.007
- ↑ 25.0 25.1 Cui D, Li G, Akpek EK. Autologous serum eye drops for ocular surface disorders. Curr Opin Allergy Clin Immunol. 2021 Oct 1;21(5):493-499. doi: 10.1097/ACI.0000000000000770. PMID: 34261888.
- ↑ Ribeiro, M. V. M. R. , Nogueira Ribeiro, E. A. , & Ribeiro, L. F. (2018). The Use of Platelet-Rich Plasma in Dry Eye Disease. In Y. Tutar, & L. Tutar (Eds.), Plasma Medicine - Concepts and Clinical Applications. IntechOpen. https://doi.org/10.5772/intechopen.76090
- ↑ 27.0 27.1 Pan Q, Angelina A, Marrone M, Stark WJ, Akpek EK. Autologous serum eye drops for dry eye. Cochrane Database Syst Rev. 2017 Feb 28;2(2):CD009327. doi: 10.1002/14651858.CD009327.pub3. PMID: 28245347; PMCID: PMC5510593.
- ↑ Shtein RM, Shen JF, Kuo AN, Hammersmith KM, Li JY, Weikert MP. Autologous Serum-Based Eye Drops for Treatment of Ocular Surface Disease: A Report by the American Academy of Ophthalmology. Ophthalmology. 2020 Jan;127(1):128-133. doi: 10.1016/j.ophtha.2019.08.018. Epub 2019 Sep 24. PMID: 31561880.
- ↑ Valencia Castillo SL, Martín ES, García Frade LJ, García-Miguel FJ. Autologous serum eye drops improve tear production, both lachrymal flow and stability tests and conjunctival impression cytology with transfer in dry eye disease. Blood Transfus. 2021 Jan;19(1):45-53. Doi:
- ↑ von Hofsten J, Egardt M, Zetterberg M. The use of autologous serum for the treatment of ocular surface disease at a Swedish tertiary referral center. Int Med Case Rep J. 2016; 9: 47–54.
