OBJECTIVE: To review the potential health risks associated with bioengineered ocular surface tissue, which serves as a bellwether for other tissues. METHODS: All clinical trials using bioengineered ocular surface tissue published between July 1, 1996, and June 30, 2005, were reviewed with respect to materials used and statements of risk assessment, risk remediation, adverse events, manufacturing standards, and regulatory oversight. RESULTS: Ninety-five percent of investigational protocols used 1 or more animal-derived products and an overlapping 95% used 1 or more donor human tissues. Consideration of risks reveals a very low probability of potential harm but a significant risk of disability or death if such an event were to occur. Details of ethics approval, patient consent, and donor serologic test results were not consistently provided. No references were made to risk assessment or to codes of manufacturing and clinical practice. CONCLUSION: While a degree of risk is associated with bioengineered ocular surface tissue, investigational reports of this new technology have yet to address issues of risk management and regulatory oversight. CLINICAL RELEVANCE: Attention to risk and codes of manufacturing and clinical practice will be required for advancement of the technology. We suggest the adoption of international standards to address these issues.

Inherent risks associated with manufacture of bioengineered ocular surface tissue

Aim This study investigated the use of the autologous technology of plasma rich in growth factors (PRGF) as a human-based substitute to fetal bovine serum (FBS) in the culture of human dental pulp stem cells. Materials & methods Stem cell characterization was performed. Analysis of isolation, proliferation, migration, trilineage differentiation, senescence and cryopreservation were compared between FBS and PRGF. Results Human dental pulp stem cell cultures isolated and maintained with PRGF showed a significantly higher number of cells per explant than FBS cultures. Cell proliferation, migration, osteogenic mineralization and adipogenic differentiation were found to be significantly higher in PRGF than FBS. Conclusion The autologous PRGF technology could be a suitable and safer substitute for FBS as a culture medium supplement for clinical translation of cell therapy.

Autologous plasma rich in growth factors technology for isolation and ex vivo expansion of human dental pulp stem cells for clinical translation.

Purpose To describe the case of a patient with a recurrent large myopic macular hole (MH), who was successfully treated with a plasma rich in growth factors (PRGF) membrane. Case Report A 71-year-old patient presented a myopic MH in his right eye. One month later, pars plana vitrectomy with internal limiting membrane (ILM) peeling was performed, achieving closure of the MH. Three months later a recurrence was observed (700 µm) without visual acuity (VA) improvement. A new surgery was carried out placing an autologous PRGF-membrane into the MH, and performing a fluid-gas exchange at the end of the surgery. After two months of follow-up, the MH was completely closed, obtaining the anatomic recovery of the foveal depression, and improving the VA to 0.1. No adverse reactions were associated with the use of PRGF and there were no new recurrences of the MH in a follow-up period of six months. Conclusion The use of PRGF-membrane can be used as adjunctive therapy in the surgical repair of recurrent large myopic MHs, thus improving anatomic and visual outcomes.

/pdf/treatment-of-recurrent-myopic-macular-hole-using-membrane-of-kmuvppxz3h.pdf

Treatment of recurrent myopic macular hole using membrane of plasma rich in growth factors.

Purpose To analyze whether plasma rich in growth factors (PRGFs) eye drops preserve their activity and biological properties after storage for 9 and 12 months at -20°C, and at 4°C, and at room temperature (RT) for 3 and 7 days in comparison to fresh samples (t0). Methods PRGF eye drops were obtained from 6 healthy donors. Then, they were stored for 9 and 12 months at -20°C. At each time, different PRGF eye drops samples were thawed and maintained at RT or at 4°C for 3 and 7 days. Platelet-derived growth factor-AB, epidermal growth factor, transforming growth factor-β1, vascular endothelial growth factor, angiopoietin-1, and thrombospondin-1 were analyzed at each time and temperature of storage. In addition, the pH level, the microbial contamination, and the proliferative potential on primary human corneal stromal fibroblasts human keratocytes of each obtained PRGF eye drops were also evaluated. Results All growth factor levels were preserved at each time and storage condition. No differences were observed on the human keratocytes proliferation after treatment with PRGF eye drops at any studied time or temperature. No microbial contamination was observed in any of the PRGF eye drops. Finally, the pH levels increased significantly after 9 and 12 months of storage at -20°C compared with t0. Conclusions 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 RT.

Short- and Long-Term Stability of Plasma Rich in Growth Factors Eye Drops.

The aim of this study was to evaluate the use of PRGF (plasma rich in growth factors) as an adjuvant to PPV (pars plana vitrectomy) in recurrent, persistent, or poor prognosis MH (macular hole). Patients with MH were treated with PPV plus adjuvant therapy (PRGF membrane (mPRGF) and injectable liquid PRGF (iPRGF)). The anatomical closure of MH and postoperative BCVA (best-corrected visual acuity) were evaluated. Eight eyes (eight patients) were evaluated: myopic MH (MMH, n = 4), idiopathic MH (IMH, n = 2), iatrogenic n = 1, traumatic n = 1. The mean age was 53.1 ± 19.3 years. Hence, 66.7% (n = 4) of patients previously had internal limiting membrane peeling. Five patients (62.5%) received mPRGF and iPRGF, and three patients (37.5%) received iPRGF. Gas tamponade (C3F8) was placed in seven cases and one case of silicone oil. Anatomic closure of MH was achieved in seven eyes (87.5%) and BCVA improved in six cases. In the MMH group, visual acuity improved in two lines of vision. Follow-up time was 27.2 ± 9.0 months. No adverse events or MH recurrences were recorded during follow-up. The use of PRGF as an adjuvant therapy to PPV can be useful to improve anatomical closure and visual acuity in MH surgery.

/pdf/plasma-rich-in-growth-factors-in-macular-hole-surgery-2kb4xjm4.pdf

Plasma Rich in Growth Factors in Macular Hole Surgery

Purpose Develop an autologous culture method for ex vivo expansion of human limbal epithelial progenitor cells (LEPCs) using Plasma Rich in Growth Factors (PRGF) as a growth supplement and as a scaffold for the culture of LEPCs. Methods LEPCs were cultivated in different media supplemented with 10% fetal bovine serum (FBS) or 10% PRGF. The outgrowths, total number of cells, colony forming efficiency (CFE), morphology and immunocytochemistry against p63- α and cytokeratins 3 and 12 (CK3-CK12) were analyzed. PRGF was also used to elaborate a fibrin membrane. The effects of the scaffold on the preservation of stemness and the phenotypic characterization of LEPCs were investigated through analysis of CK3-CK12, ABCG-2 and p63. Results LEPCs cultivated with PRGF showed a significantly higher growth area than FBS cultures. Moreover, the number of cells were also higher in PRGF than FBS, while displaying a better morphology overall. CFE was found to be also higher in PRGF groups compared to FBS, and the p63-α expression also differed between groups. LEPCs cultivated on PRGF membranes appeared as a confluent monolayer of cells and still retained p63 and ABCG-2 expression, being negative for CK3-CK12. Conclusions PRGF can be used in corneal tissue engineering, supplementing the culture media, even in a basal media without any other additives, as well as providing a scaffold for the culture.

Autologous method for ex vivo expansion of human limbal epithelial progenitor cells based on plasma rich in growth factors technology

Background Plasma rich in growth factors (PRGF-Endoret) is an autologous platelet enriched plasma that has been standardised for ophthalmic application. In the past years, PRGF-Endoret has been successfully used like an eye drop for the treatment of a wide range of ocular surface diseases, including dry eye, persistent corneal epithelial defects and ulcers. Current classification of autologous plasma derivatives such as human medicines imply that it has to meet all the requirements of ophthalmic preparations. Purpose To assess the galenic properties of the PRGF eye drops and its compliance with European Pharmacopoeia requirements. Material and methods Eye drops were obtained using the PRGF-Endoret ophthalmology kit. Briefly, blood was collected into 9 mL tubes, centrifuged at 580 g, plasma column was drawn off avoiding the buffy coat and incubated at 37°C with CaCl 2 . Supernatants were collected, filtered and aliquoted in single dose containers. Eye drops were kept fresh or stored at −20°C for 3 months. Aseptic process simulations (Media Fill) were performed using tryptic soy broth (TSB) to 6 batches. The samples were incubated for 14 days and inspected for microbial growth. A growth promotion test was done. Deliverable volume test was applied to 5 single dose containers. Oat-Water tightness test was done in two batches in duplicate with a toluidine solution and applying a vacuum for 10 min. pH and osmolarity were assessed in fresh samples and after freezing for 3 months. Results In the media fill all units were negative for growth. In the growth promotion test, growth of all the microorganisms was clearly seen. The volume of each container was within the range of 95–110%. In the first batch, no toluidine was detected inside the vials or the caps. In the second batch, only one vial had a shadow of toluidine inside the cap. pH and osmolarity values were slightly modified after freezing. Eye drops were clear and free from particles. Conclusion The PRGF-Endoret method was aseptic The water tightness of the vials was correct, and the deliverable volume corresponded with the nominal volume. pH and osmolarity remained constant during the whole period. We can affirm that PRGF-Endoret meets the European Pharmacopoeia requirements and their galenic properties. Conflict of interest: Corporate sponsored research or other substantive relationships: EA is the scientific director of BTI, and GO and FM are scientists at BTI.

https://ejhp.bmj.com/content/ejhpharm/24/Suppl_1/A204.1.full.pdf

PP-006 Galenic properties of plasma rich in growth factors eye drops

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Autologous method for ex vivo expansion of human limbal epithelial progenitor cells based on plasma rich in growth factors technology

PP-006 Galenic properties of plasma rich in growth factors eye drops