title: Toxicity of a biodegradable microneedle implant loaded with methotrexate as a sustained release device in normal rabbit eye: a pilot study.
abstract: OBJECTIVE
  Primary intraocular lymphoma is a term that refers to nonmetastatic malignant lymphoid neoplasia that arises primarily within the eye. Primary vitreo-retinal lymphoma (PVRL), a subtype of primary intraocular lymphoma that comprises at least 85% of cases, provides a therapeutic challenge because of its diverse clinical presentations and variable clinical course. One of the currently available treatment options for PVRL is intravitreal injection of methotrexate. To achieve and maintain sufficient therapeutic levels of methotrexate in the eye to eradicate PVRL, the patient must undergo multiple intravitreal injections with attendant potential toxic peaks and sub-therapeutic troughs of intraocular drug concentrations. In this pilot study, we investigated the intravitreal concentration of methotrexate over time, and toxicity associated with slow sustained release of the drug from a biodegradable device containing methotrexate implanted in a deep scleral pocket of the eyes of normal rabbits.
  
  
  METHODS
  Biodegradable microneedle implants (~8 mg) loaded with 10%wt of methotrexate were fabricated using solvent cast method. All the implants were inserted surgically in a deep lamellar scleral pocket created in each eye of 3 albino New Zealand rabbits. The left eye received a placebo implant, and the right eye received an implant loaded with methotrexate. Postoperatively, the animals were monitored regularly for complications related to the surgery, implant, or drug. The animals were sacrificed 4 weeks after the surgical implantation, and the eyes were enucleated. The eyes were studied histopathologically to look for evidence of inflammation related to the implants and toxicity related to the implant or drug.
  
  
  RESULTS
  The biodegradable microneedle methotrexate implants were inserted successfully into deep lamellar scleral pockets of the rabbits without any intraoperative or postoperative complications. Histopathologic examination of the medicated (methotrexate implant) and nonmedicated devices (placebo) showed no evidence of drug toxicity. Also, no major differences were apparent between the eyes as well as no acute ocular inflammation or infection was evident around the implantation site.
  
  
  CONCLUSIONS
  This sustained release implant containing methotrexate proved to be nontoxic histopathologically and well-tolerated in the eyes of normal rabbit.
authors.affiliation: Department of Mechanical Engineering, University of Cincinnati, OH 45221, USA.
authors.forename: Nikhil Kumar
authors.initials: NK
authors.lastname: Palakurthi
authors.forename: Zelia M
authors.initials: ZM
authors.lastname: Correa
authors.forename: James J
authors.initials: JJ
authors.lastname: Augsburger
authors.forename: Rupak K
authors.initials: RK
authors.lastname: Banerjee
mesh_terms: D020341:Absorbable Implants / Q000009:adverse effects*; D000818:Animals; D003692:Delayed-Action Preparations; D005123:Eye / Q000187:drug effects* / Q000473:pathology; D005134:Eye Neoplasms / Q000188:drug therapy; D058449:Intravitreal Injections; D008223:Lymphoma / Q000188:drug therapy; D008727:Methotrexate / Q000008:administration & dosage* / Q000633:toxicity*; D010865:Pilot Projects; D011817:Rabbits
chemical_list: D003692:Delayed-Action Preparations; D008727:Methotrexate