Blood-derived preparations are a general term for biologics obtained by centrifuging and activating human blood. Platelet alpha granules store platelet-derived growth factor (PDGF), epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF), nerve growth factor (NGF), insulin-like growth factor (IGF), etc. These molecules interact with receptors in the tissue microenvironment, reducing inflammation and promoting wound healing.
The use of blood-derived preparations in ophthalmology has developed in the ocular surface field. Case series have been reported using a mobile ocular perfusion pump to supply serum or plasma to the ocular surface. Since then, following the introduction of autologous serum, platelets have been shown to be major contributors to tissue regeneration, leading to the development of platelet-rich plasma (PRP) products.
Blood-derived eye drops are positioned as an emerging therapy that mimics the function of natural tears and increases the concentration of active growth factors and mediators 3). Autologous serum, umbilical cord serum, and platelet-rich plasma (PRP) have also demonstrated beneficial effects for persistent corneal epithelial defects 4).
Blood-derived preparations are used for the following eye diseases. Moderate to severe dry eye syndrome is the most common indication, and they are also used for severe cases associated with Sjögren’s syndrome and graft-versus-host disease (GVHD) 3). Persistent corneal epithelial defect (PED) is one of the main indications because high concentrations of EGF contribute to epithelial regeneration and stabilization. Neurotrophic keratitis (NK), corneal ulcers/descemetocele, and ocular surface disorders after refractive surgery are also treated.
In chronic GVHD, 50-70% of bone marrow transplant patients develop it, and the most frequent ocular complication is keratoconjunctivitis sicca (KCS) 1). PRGF membranes and autologous serum are used for persistent corneal erosion and corneal thinning associated with severe KCS 1).
Typical findings in patients eligible for treatment include positive corneal fluorescein staining, shortened tear film breakup time (TBUT), decreased Schirmer test values, conjunctival hyperemia, and persistent corneal epithelial defects. Severe cases show corneal ulcers, corneal thinning, and increased risk of perforation.
It is used for ocular surface diseases that do not respond adequately to conventional treatments, such as moderate to severe dry eye resistant to standard therapies including artificial tears and cyclosporine eye drops, persistent corneal epithelial defects that do not heal with usual treatment, neurotrophic keratitis, and corneal ulcers.
Autologous serum has a complex composition similar to natural tears. Tears contain growth factors such as EGF, NGF, TGF-α, keratinocyte growth factor, and IGF-1, as well as vitamins A and E, fibronectin, and over 1500 proteins 3). Serum also contains these components, which inhibit apoptosis and promote epithelial cell proliferation and differentiation 3).
The therapeutic effect of platelet-rich plasma (PRP) is based on the release of PDGF and TGF-β from platelet alpha granules. These induce fibroblast mitosis and collagen synthesis, promoting epithelialization. PRGF is a leukocyte-free platelet concentrate that differs from other preparations in that it reduces inflammatory reactions.
PRGF has anti-inflammatory, anti-fibrotic, bacteriostatic, and anti-apoptotic effects 2). PRGF inhibits the differentiation of corneal stromal fibroblasts into myofibroblasts, significantly reducing scar formation after wound healing 2). In vitro and in vivo studies have shown superior results in corneal wound closure and corneal epithelial cell proliferation and migration compared to autologous serum 2).
Autologous Serum / Allogeneic Serum
Autologous serum eye drops are prepared from serum obtained by centrifuging the patient’s own whole blood. They are used at dilutions of 20–100%. Allogeneic serum is obtained from healthy donor blood and serves as an alternative for patients who cannot undergo autologous blood collection 3).
Platelet-Rich Plasma (PRP)
Whole blood is mixed with an anticoagulant (sodium citrate) and centrifuged to extract the platelet-concentrated plasma fraction. It has been reported that OSDI scores improved in 87.5% of patients and corneal staining decreased in 76.1% 3).
Plasma Rich in Growth Factors (PRGF)
It is a subtype of PRP from which leukocytes have been removed. Activation with calcium chloride catalyzes the coagulation cascade, enabling the release of growth factors and formation of a fibrin network 2). It is used in forms such as eye drops, clots, and membranes.
| Preparation | Key Points of Preparation Method | Main Features |
|---|---|---|
| Autologous serum | Centrifugation → serum collection | Tear-like components |
| PRP | Anticoagulant + centrifugation | High concentration of platelets |
| PRGF | PRP + Ca activation | Leukocyte-free |
| UCS | Prepared from umbilical cord blood | High concentration of growth factors |
| FAB | Finger prick | Simple and low cost |
Umbilical cord serum (UCS) contains higher concentrations of EGF, TGF-β, NGF, and substance P than autologous serum 3). It is stable for up to 1 month at 4°C and 3 months at −20°C 3). A large amount of serum can be collected from the umbilical vein at one time, eliminating the need for repeated blood draws 3).
In the preparation of PRGF membranes, the patient’s blood is centrifuged to separate the plasma fraction, which is then activated with calcium chloride and thrombin 2). Incubation at high temperature converts soluble fibrinogen into an insoluble fibrin membrane 2). This membrane, containing growth factors such as EGF, PDGF-AB, TGF-β1, VEGF, IGF-I, and FGF, is sutured into the tissue defect 2).
PRP refers to plasma enriched with platelets in general and may contain white blood cells. PRGF is a subtype of PRP that is prepared by removing white blood cells and activating with calcium chloride. Because it does not contain white blood cells, it induces less inflammation, is rich in growth factors, and has high concentrations of anti-inflammatory molecules. It can be used in various forms such as eye drops, clots, and fibrin membranes.
A Cochrane review of autologous serum eye drops showed potential short-term symptom improvement compared to tear substitutes 3). A meta-analysis of 7 RCTs reported higher efficacy in symptoms and multiple objective findings 3). The EULAR task force recommends the use of autologous serum eye drops for cases inadequately managed with artificial tears or cyclosporine 3).
In a case series of 368 patients using PRP eye drops, 87.5% showed significant improvement in OSDI scores and 76.1% showed reduction in corneal staining after 6 times daily for 6 weeks 3). In 15 patients with Sjögren’s syndrome who received lacrimal gland PRP injections, all patients showed decreased corneal staining, increased Schirmer values, and improved TBUT at 90 days 3).
Autologous Serum vs. PRP
In a 96-patient RCT, there were no significant differences between groups in OSDI, TBUT, corneal staining, or Schirmer values after 4 weeks of treatment 3). PRP has a shorter preparation time and is a useful alternative for Sjögren’s syndrome 3).
Effects of PRGF
In a multicenter retrospective study of 61 DED patients, corneal epithelial damage and subjective symptoms significantly improved 3 months after using PRGF eye drops, and 74.3% showed improvement in corneal staining 3). The PRGF treatment group also showed improvement in corneal nerve plexus morphology 3).
A network meta-analysis found that platelet lysate or PRP improved OSDI and corneal staining more than autologous serum, but the certainty of evidence was rated as “low” 3).
In 40 cases of persistent corneal epithelial defects that did not heal after amniotic membrane transplantation, serum eye drops were used, and improvement in healing and visual recovery was reported compared to artificial tears 3). PRGF is a safe and effective option for stage 2–3 neurotrophic keratitis, showing high healing rates in a short period. For corneal ulcers, PRGF membrane is used alone or in combination with amniotic membrane.
In the use of PRGF membrane for corneal dellen (pediatric cases), the membrane was absorbed within 3 weeks postoperatively, and the dellen disappeared after 1 month 2). For severe KCS associated with cGVHD, full-thickness corneal transplantation and PRGF membrane use have been reported, but there are also refractory cases complicated by severe calcific corneal degeneration 1).
Autologous platelet-rich plasma (A-PRP) has been used in the surgical treatment of idiopathic macular holes since 1995. For very large macular holes, it is presumed to enhance glial proliferation and ensure hole closure. Preliminary results of sub-Tenon injection of A-PRP for retinitis pigmentosa have shown significant improvements in visual function and multifocal electroretinogram values.
PRGF eye drops can be frozen for up to 12 months without significant loss of major growth factors and proteins. Biological activity is maintained for 3–7 days at 4°C or room temperature. Umbilical cord serum is stable for up to 1 month at 4°C and 3 months at −20°C. Lyophilized PRGF eye drops maintain their properties for at least 3 months at room temperature or 4°C.
The therapeutic effects of blood-derived products are based on multilayered mechanisms. PDGF, EGF, FGF, TGF-β, NGF, and IGF released from platelet α-granules bind to cell surface receptors, activating signaling pathways involved in proliferation, migration, and differentiation.
Fibrin crosslinks tissue gaps and serves as a scaffold for cell proliferation and migration 2). PRGF membrane utilizes this fibrin crosslinking effect and has been used in preclinical studies as a bioadhesive for treating deep corneal ulcers and in lamellar keratoplasty 2).
A unique mechanism of PRGF is that it is leukocyte-free, thus suppressing the release of inflammatory cytokines. This prevents corneal stromal fibroblasts from differentiating into myofibroblasts, significantly inhibiting scar and haze formation 2). Furthermore, the bacteriostatic action of PRGF provides a protective effect against gram-positive bacteria.
PRGF has been shown in vitro to reduce cytotoxicity and maintain mitochondrial activity and cell viability in retinal pigment epithelial (RPE) cells under oxidative stress.
The TFOS DEWS III report positions blood-derived eye drops as an emerging approach for dry eye treatment, summarizing evidence of efficacy from RCTs and meta-analyses 3). Both autologous serum and allogeneic serum have shown improvements in symptoms and objective findings, but standardization of preparation methods and widespread adoption remain challenges 3).
Fingertip autologous blood (FAB) is attracting attention as an innovative method 3). In a multicenter RCT, applying FAB four times daily in addition to conventional therapy significantly improved OSDI scores 3). A prospective case series of 16 patients also reported improvements in corneal staining, TBUT, visual acuity, and ocular comfort 3). It is patient-friendly and low-cost, but the effect diminishes four weeks after treatment discontinuation, which is a challenge 3).
In the field of refractive surgery, PRGF has been shown to induce nerve regeneration after LASIK, reducing the onset of dry eye, and to stimulate corneal wound healing after PRK, decreasing haze formation. Future needs include international standardization of preparation protocols, large-scale RCTs with long-term follow-up, and establishment of a classification system for platelet preparations.
This method involves pricking the fingertip to collect a small amount of autologous whole blood and applying it directly to the ocular surface. It does not require complex preparation such as blood collection and centrifugation, and can be easily performed by the patient. A multicenter RCT has confirmed its additive effect to conventional therapy, but the effect diminishes after discontinuation, requiring continuous use.
