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Julien Bérard, John Zupancich, Audrey Hecka, George Mihov, Sarah Reiver, Jens Thies, Kenneth Messier, Barbara Wirostko, MaryJane Rafii; Delivery of Human Growth Hormone via DSM’s Poly(ester amide). Invest. Ophthalmol. Vis. Sci. 2013;54(15):5049.
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Fibrillar, degradable polymer-based constructs for the local, sustained delivery of recombinant human growth hormone (rhGH) were generated. The safety, tolerability and possible efficacy of subconjunctivally placed devices was evaluated in a rabbit debridement model. rhGH was selected based on an ability to up-regulate and modulate various growth factors (i.e., insulin growth factor, epidermal growth factor) that have been shown to be involved in corneal re-epithelialization.
rhGH-loaded, multi-layer constructs were prepared via encapsulation of solid protein within poly(ester amide) (PEA) matrices through use of an innovative film formation and assembly process. Constructs were subsequently shaped into fibers with dimensions that facilitate passage through a 27 gauge needle. Construct in vitro release performance was evaluated over a period of 30 days and the bioactivity of released rhGH confirmed via a proliferative cell assay. In vivo experiments compared PEA/rhGH (~12ug/device) and PEA (i.e., blank) constructs placed subconjunctival, perilimbal to BSS and topical rhGH (100ug/ml) delivered four times daily in a standardized rabbit corneal epithelial debridement model (N=9, 18 eyes). Safety, tolerability, and efficacy were assessed daily and histopathology was performed on Day 7. Time to complete healing and daily percent healing was compared across arms over 7 days.
In vitro results demonstrate that over 90% of rhGH encapsulated within early generation PEA fibers is released over the course of 3 days. Advances in multi-layer construct design reveal the potential to sustain the release of rhGH for multiple weeks. In vivo results showed PEA/rhGH and PEA constructs were well tolerated, with histopathology on all eyes revealing normal healing with no inflammation or angiogenesis. An efficacy signal was difficult to ascertain due to the small number of animals utilized in the current study, and the rapid healing that occurs in normal healthy rabbits.
Subconjunctivally placed rhGH-loaded PEA fibers were well tolerated in vivo and no histopathologic concerns were identified. In order to test efficacy, a preclinical model of impaired wound healing, such as an alkali burn, should be utilized. Study results indicate that PEA could be a viable polymer for the sustained delivery of proteins to the eye.
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