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Bioengineered Human Stromal Lenticule for Recombinant Human Nerve Growth Factor Release: A Potential Biocompatible Ocular Drug Delivery System.

ABSTRACT: Small incision lenticule extraction (SMILE), is a surgical procedure for the myopia correction, during which a corneal stromal lenticule is extracted. Given that we have previously demonstrated how this discarded tissue could be repurposed as a bio-scaffold for stromal engineering, this study aimed to explore its use as an ocular drug delivery system of active molecules, using neurotrophic factor Nerve Growth Factor (NGF). We employed human stromal lenticules directly collected from healthy donors undergoing SMILE. Following a sodium dodecylsulfate (SDS) treatment, decellularized lenticules were incubated with a suspension of polylactic-co-glycolic-acid (PLGA) microparticles (MPs) loaded with recombinant human NGF (rhNGF-MPs). Fluorescent MPs (Fluo-MPs) were used as control. Data demonstrated the feasibility to engineer decellularized lenticules with PLGA-MPs which remain incorporated both on the lenticules surface and in its stromal. Following their production, the in vitro release kinetic showed a sustained release for up to 1 month of rhNGF from MPs loaded to the lenticule. Interestingly, rhNGF was rapidly released in the first 24 h, but it was sustained up to the end of the experiment (1 month), with preservation of rhNGF activity (around 80%). Our results indicated that decellularized human stromal lenticules could represent a biocompatible, non-immunogenic natural scaffold potential useful for ocular drug delivery. Therefore, combining the advantages of tissue engineering and pharmaceutical approaches, this in vitro proof-of-concept study suggests the feasibility to use this scaffold to allow target release of rhNGF in vivo or other pharmaceutically active molecules that have potential to treat ocular diseases.

SUBMITTER: Mastropasqua L

PROVIDER: S-EPMC9260024 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeThe purpose of this study was to explore the optimal shape of customized lenticules for stromal lenticule addition keratoplasty (SLAK) for off-centered ectasia.MethodsTwo different methods to create ex vivo models of eccentric-keratoconus were investigated. Twelve human corneas were used to create model 1 by a hyperopic photorefractive keratectomy (PRK), and model 2 by masked phototherapeutic keratectomy (PTK) on the anterior corneal surface, whereas both types received myopic ablation of the posterior surface. Keratoconus models underwent a modified femtosecond laser (FSL) flap-cut to create stromal pockets. Sixteen human corneas underwent FSL dissection to obtain four lenticule types: type I (planar) and type II (negative) lenticules were used without modifications, whereas type III (customized-planar), and type IV (customized-negative) lenticules underwent further masked-PRK to obtain an asymmetric bow-tie shape. Topographic, aberrometric analysis, and anterior segment optical coherence tomography (AS-OCT) were performed in all recipient corneas before and after lenticule implantation.ResultsKeratoconus model was successfully reproduced. Tomographic analysis showed a significant inferiorly decentered corneal steepening with coherent stromal thinning. Model 2 reproduced better the curvature of real keratoconus. Lenticules type I implantation induced a homogeneous corneal thickening, type III produced higher thickening in the inferior half of the cornea. Type II determined a maximal peripheral pachymetric increase, with a gradual reduction toward the center, and type IV presented an asymmetric peripheral thickening. Topographic assessment showed a cone apex flattening in all cases, but it was significantly higher in types II and IV. Customized lenticules improved significantly corneal surface regularity regarding types I and II.ConclusionsThe approach of customizing lenticules by increasing their asymmetry and tailoring the re-shaping effects, may improve SLAK outcomes in eccentric keratoconus.

Project description:Purpose:To introduce cases of the use, as patch grafts, of stromal lenticules obtained by small incision lenticule extraction (SMILE) surgery. Observations:Case 1 was a 79-year-old man who presented with Ahmed-valve-tube exposure in his left eye. His uncorrected visual acuity (UCVA) was 20/40, best-corrected visual acuity (BCVA) 20/32, and intraocular pressure (IOP) 11?mmHg. He was treated with stromal lenticule patch that had been extracted by SMILE surgery. The patch was positioned underneath of the conjunctiva and sutured to it. At postoperative 8 months, the graft site was well maintained without Ahmed valve-tube exposure, the UCVA was 20/32, BCVA 20/20, and IOP 12?mmHg.Case 2 was a 60-year-old man who presented with Ahmed-valve-tube exposure in his right eye. His UCVA was finger-count (FC) 30 cm, his BCVA 20/125, and his IOP 14?mmHg. He was treated with stromal lenticule patch by the same method as employed in case 1. At postoperative 10 days, tube re-exposure and displacement of the Ahmed valve external plate toward the limbus area occurred due to loosening of the anchoring suture. So, we removed the Ahmed valve device, which had been implanted in the supero-temporal area, and performed new Ahmed valve implantation, with a stromal lenticule flap instead of a partial scleral flap, in the supero-nasal area. As of 6 months post-reoperation, the patient was stable, with UCVA 20/200, BCVA 20/40 and IOP 13?mmHg.Case 3 was a 74-year-old man who presented with bullous keratopathy in his right eye, which was blind. Due to severe adhesions, his conjunctiva could not cover the entire cornea. Therefore, we performed a stromal lenticule patch graft with conjunctival advance flap. At postoperative 3 months, the patient's right eye was stable, without displacement or melting of the lenticule graft. Conclusions & importance:It is suggested that the stromal lenticule, with its biocompatibility, sufficient strength, ease of handling and low cost, is a useful patch graft for various therapeutic purposes in the ophthalmic field.

Project description:IntroductionResection and reconstruction of the esophagus remains fraught with morbidity and mortality. Recently, data from a porcine reconstruction model revealed that segmental esophageal reconstruction using an autologous mesenchymal stromal cell-seeded polyurethane graft (Cellspan esophageal implant [CEI]) can facilitate esophageal regrowth and regeneration. To this end, a patient requiring a full circumferential esophageal segmental reconstruction after a complex multiorgan tumor resection was approved for an investigational treatment under the Food and Drug Administration Expanded Access Use (Investigational New Drug 17402).MethodsAutologous adipose-derived mesenchymal stromal cells (Ad-MSCs) were isolated from the Emergency Investigational New Drug patient approximately 4 weeks before surgery from an adipose tissue biopsy specimen. The Ad-MSCs were grown and expanded under current Good Manufacturing Practice manufacturing conditions. The cells were then seeded onto a polyurethane fiber mesh scaffold (Cellspan scaffold) and cultured in a custom bioreactor to manufacture the final CEI graft. The cell-seeded scaffold was then shipped to the surgical site for surgical implantation. After removal of a tumor mass and a full circumferential 4 cm segment of the esophagus that was invaded by the tumor, the CEI was implanted by suturing the tubular CEI graft to both ends of the remaining native esophagus using end-to-end anastomosis.ResultsIn this case report, we found that a clinical-grade, tissue-engineered esophageal graft can be used for segmental esophageal reconstruction in a human patient. This report reveals that the graft supports regeneration of the esophageal conduit. Histologic analysis of the tissue postmortem, 7.5 months after the implantation procedure, revealed complete luminal epithelialization and partial esophageal tissue regeneration.ConclusionsAutologous Ad-MSC seeded onto a tubular CEI tissue-engineered graft stimulates tissue regeneration following implantation after a full circumferential esophageal resection.

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Bioengineered Human Stromal Lenticule for Recombinant Human Nerve Growth Factor Release: A Potential Biocompatible Ocular Drug Delivery System.

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