Blood Derivatives in Ophthalmology
The use of several blood-derived formulations to perform diverse treatments has been a common trend in the last years in regenerative medicine.  The healing mechanism constitutes a complex process where a matrix supports the newly growing tissue, under the mediation of several biological mediators including growth factors. The knowledge of healing pathways and the interplay of growth factors and fibrin polymerization for structural reconstruction has allowed the development of more specific tools to improve and accelerate regeneration in a wide range of pathologies. Human blood derivatives as autologous serum have shown potential due to regenerative properties. The first description of blood derivates use in ophthalmology occurred in 1975 in a case series by Ralph and colleagues, in which a mobile ocular perfusion pump delivered serum or plasma to the ocular surface. Thenceforth, several formulations have been described with the purpose of improving regeneration, especially in surface eye diseases. After autologous serum use, platelets have been shown to be the principal contributor to tissue regeneration, leading to a broad range of platelet-rich plasma (PRP) products to enhance healing processes. A wide range of biologically active agents is stored in platelet granules. Growth factors such as 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), as well as cytokines and chemokines, constitute examples of these biologic agents. The interaction between these molecules and their respective receptors in the tissue microenvironment can lead to overall reduced inflammation and the activation of growth-related signaling pathways that facilitate wound healing. PRP, also known as Autologous Platelet Gel, constitutes a gel with a high concentration of autologous platelets suspended in a small volume of plasma, produced by centrifugation of the blood of the patient. PRP has proved to accelerate epithelialization. PDGF, TGFβ, and other tissue GF are released from platelet alfa granules, inducing fibroblastic mitosis and collagen synthesis. A huge amount of PRP protocols have been described, with several applications and different results. The primary form of the PRP is generated initially by isolating and concentrating platelets into small amounts of plasma. Subsequently, additional methods have been described to produce PRP and further platelet-derived products including leukocyte-rich PRP (L- PRP, LR-PRP or W-PRP), platelet concentrated plasma (PCP), non-coagulating platelet-derived factor concentrate (PFC), platelet gel (PG), platelet lysate (PL), platelet-rich fibrin (PRF), and platelet-rich growth factors (PRGF). It is highly likely that through fresh research, more products and applications will continue to expand. More recently, RPR with lack of leukocytes (PRGF), produced by a controlled platelet-fibrinogen activation set, has gained more relevance due to the versatile formulations and long-term biostability. PRGF consists of a platelet-enriched plasma free of leukocytes that contains hemostatic fibrin and a pool of proteins and growth factors. PRGF preparation also includes blood extraction and centrifugation, besides separation of plasma fractions. Centrifugation separates blood components creating an upper layer of the plasma followed by a thin leukocyte layer (buffy coat) and the erythrocyte layer at the bottom. At the top of the plasma column, there is a low concentration of platelets, whereas the bottom portion contains a higher concentration. Then, calcium-based activation catalyzes the coagulation pathways allowing both the release of the growth factors and the formation of a polymerized fibrin meshwork. Depending on the time elapsed after platelet activation, different formulations can be obtained with several therapeutic purposes: injectable PRGF (iPRGF), PRGF clot (cPRGF), PRGF membrane (mPRGF), PRGF eye drops or supernatant PRGF (ePRGF). Since PRGF is a leukocyte lacking coagulation, pro-inflammatory responses are reduced , justifying its more spread use compared to the different formulations.
Several in vitro and pre-clinical studies have been performed to determine the biological, biomechanical and stability properties as well as the biochemical pathways triggered by PRF formulations on ocular cells. It has been proven that platelets rich components stimulate cell proliferation and migration. Furthermore, PRGF has proven to have anti-inflammatory, antifibrotic, bacteriostatic, and antiapoptotic effects.  All the ophthalmologic topic therapies have the need to be safe, without risk of contamination and further infections. Furthermore, for a practical way of use, the functionality of the application and preservation is also an important point. Globally, these concerns relate both to biologic products to administer and to the long-term use of drop dispensers. Evidence has shown that PRGF eye drops can be stored for up to 12 months without reduction of the main growth factors and proteins and without any microbial contamination. Furthermore, the biological activity of the PRGF eye drops is maintained after storing for 3 and 7 days at 4°C or at room temperature, allowing its practical use for the normal population. Also, Freeze-dried plasma rich in growth factors eye drops preserve the main growth factors and their biological activity after storage at room temperature or 4°C for up to 3 months. Lyophilized plasma rich in growth factors eye drops conserve their biological features even without the use of lyoprotectants for at least 3 months. Frequently, PRGF eye drops are used on a 3-month basis, using 32 eye drop multi-dispensers for a 48–72 h treatment.
Eye surface Diseases
PRF and derivates in ophthalmology have started to earn visibility in surface eye diseases, especially in the severe forms of dry eye syndrome. Several studies present the results of blood derivates on the treatment of moderate to severe dry eye syndrome      A recent review and meta-analysis concluded that biological tear substitutes, including autologous serum, autologous platelet lysate, PRP, and cord blood serum, show some efficacy in relieving dry eye symptoms without increasing adverse events. However, there remains uncertainty around these findings because of the low certainty of evidence. Besides the use of blood derivates as eye drops, injection of PRP in the lacrimal gland has also been shown to be a technique in the treatment of severe dry eye with improvement of tear film parameters through subjective and objective assessment.  Notwithstanding, this is a new technique under investigation, requiring further studies to standardize and confirm the results. Among dry eye syndrome and related diseases, blood derivatives have also been used in inflammatory conditions such as Sjogren Syndrome , graft versus host disease   , and even in eye surface disease caused by glaucoma treatments. Ocular surface disease constitutes one of the most common complications after refractive surgery. PRF and especially PRGF have been shown to be effective in improving symptoms after LASIK    and PRK. Furthermore, it has been shown to induce nerve regeneration lowering dry eye development after LASIK  and stimulating of corneal wound healing, reducing haze formation after PRK surgery. Blood derivatives have also been successfully used to improve eye surface during several different surgeries, including glaucoma surgery , strabismus  and pterygium surgery.  Its use was also tried in blepharoplasty to reduce post-surgery inflammation and edema but did not find clinical significance.
Corneal diseases have also been also studied for the regenerative properties of blood derivatives. Persistent epithelial defects are among the most common applications, due to the importance of high concentration of platelet-contained growth factors, most notably EGF, that is purported to regenerate and stabilize the newly formed epithelium, lowering relapses.    A study also demonstrated this effect in epithelial defects post keratoplasty. Neurotrophic keratitis (NK) is another therapeutic target for blood derivatives. Sanchez-Avila et al showed PRGF eye-drops could be a safe and effective therapeutic option for patients with stages 2-3 of NK, showing high rates of corneal defect/ulcer resolution in short times, either in reducing signs and symptoms of NK, and therefore preventing the progression of NK to greater ocular complications. Also, subconjunctival infiltration with autologous PRGF can be considered an effective, straightforward, and economical form of treatment for burns of the ocular surface.   Corneal ulcers have also been improved with autolous serum, PRF and PRGF.   Specifically, in descemetocele or high risk of perforation ulcers, PRGF may be used as a membrane even isolate  or combined with amniotic membrane  to improve healing. Temporary PRF membrane grafting may be an alternative intervention to avoid impending corneal perforation in cases with severe descemetocele. The further combination of amniotic membrane implant and platelet-rich plasma in both the clot and eye drop forms is an effective and easily accessible method for the primary management of corneal perforations. Unique reports have also been published, showing promises for its use for incubation of corneal grafts , and its adhesive properties for lamellar keratoplasties. In 2019, Alio et al also reported the first case in the literature of resolution of Descemet membrane rupture in acute corneal hydrops after intracameral PRP Injection. In this case, intraocular E-PRP was a promising, apparently safe, and effective treatment option in management of corneal hydrops, in which conventional approaches failed.
The high concentration of growth factors and cytokines also lead to the investigation of blood derivatives for retinal diseases, including degenerative and genetic diseases. Since 1995, autologous platelet-rich plasma (APRP) has been used successfully in the surgical treatment of full-thickness macular holes (MH).    However, a randomized trial published in 1999 did not confirm the benefits of APRP. More recent evidence shows that the use of APRP significantly improves the anatomical and functional results of the treatment of idiopathic MH. In very large MHs, APRP presumably enhances glial proliferation, which ensures their closure.    Other vitreoretinal surgery approaches are also described in the literature. Some authors describe the vitreoretinal surgical technique of using autologous platelet-rich plasma to aid in surgical repair of optic pit maculopathy refractive to previous vitrectomy.  Furthermore, a recent case report presented a modified surgical technique, based on a combination of human amniotic membrane (hAM) patch and autologous PRP in a case of recurrent retinal detachment due to a perivascular retinal hole over an area of staphyloma in an eye with pathologic myopia.
Besides an adjunct for healing in vitreoretinal surgeries, blood derivative effects have been explored for degenerative diseases characterized by cellular death. A recent study analyzed the effectiveness of PRGF in reducing the oxidative stress induced by blue light exposition on retinal pigment epithelial (RPE) cells and concluded that that PRGF treatment reduces the cytotoxic effects induced in RPE cells exposed to an oxidative stress environment. Furthermore, PRGF treatment preserves the mitochondrial activity and cell viability of RPE cells subjected to oxidative stress. Having this in mind, PRGF was studied as a potential therapy for retinitis pigmentosa (RP). Studies demonstrated that The PRP treatment has a favorable effect on visual functions in patients with RP. This approach is promising and it is safe and easy to apply. Preliminary clinical results are encouraging in terms of statistically significant improvements in visual function, mfERG values, and microperimetry. The subtenon injection of aPRP seems to be a therapeutic option for treatment and might lead to positive results in the vision of RP patients. Long-term results regarding adverse events are unknown. There have not been any serious adverse events and any ophthalmic or systemic side effects for 1 year follow-up. However, further studies with long-term follow-up are needed to determine the duration of efficacy and the frequency of application.
Although the exponent investigation and the huge and crescent clinical applications, the rapid development in platelet research has not been without challenges and a few drawbacks need to be considered. First, this is a therapy that needs laboratory structure. Physical conditions with the right equipment as well as experienced teams are required for product preparation. Only well-designed protocols allow the security and biostability of the products (5). Furthermore, variation in method preparation, confusing terminology, and unclear classification and reporting requirements for existing products have made it difficult for both scientists and clinicians to evaluate function and efficacy across published papers (5). There is a crescent difficult to compare results among studies and conclude on the better solutions. Therefore, there is an urgent need to reach an international consensus on a standardized reporting system on platelet products.
The global evidence shows research and clinical studies have shown that platelet-derived products are likely to provide a superior healing effect in the treatment of ocular surface diseases compared to standard, currently available treatments (1, 2, 5).   This suggests an ongoing and possible increasing role for platelets and derived products in clinical treatments. The awareness of these products is essential to wider recognition and approach in clinical practice. On the other hand, associated challenges, limitations, and potential risks need to be considered to prepare a better and safer product for wider and standardized use in clinics.
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