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MaryJane Rafii, Barbara Wirostko, Liliana Werner, Nick Mamalis, Thomas Zarembinski, Stacy Pritt, Glenwood Gum; Hystem, a bio-absorbable protein delivery polymer: safety, tolerability and efficacy in a rabbit corneal debridement model. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5048.
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© ARVO (1962-2015); The Authors (2016-present)
HyStemTM (BioTime, CA), a biodegradable hyaluronic acid (HA)-based polymer shown to promote wound healing, can be used for local, ocular sustained delivery of proteins. Safety, tolerability, and efficacy of this polymer, alone and in combination with recombinant human growth hormone (rhGH) to accelerate wound healing, was evaluated in a rabbit corneal debridement model (CDM). rhGH was selected based on its ability to activate growth factors, e.g., Insulin-like Growth Factor and Epidermal Growth Factor, that have been shown to be involved in corneal re-epithelialization.
To assess the tolerability of HyStem cross-linked with glutathione (GSSG); non-cross-linked HyStem, HyStem/GSSG, and Ringers lactate (RL) (control) were applied four times a day (QID) for 4 days topically in a CDM using New Zealand rabbits (NZR)( N=3, 2 eyes/arm). Twice daily, slit lamp exams with photos were employed to evaluate healing. Tissues were harvested on day 5 and histopathology was performed. To evaluate the efficacy of HyStem/GSSG/rhGH in accelerating wound healing, a validated NZR CDM model (N=11) was used. All 22 eyes received topical dexamethasone (dex) QID for 7 days, alone (control; n=8 eyes), with HyStem/GSSG BID (n=4 eyes), or with HyStem/GSSG/rhGH BID (4 μg/50 μL drop; n=10 eyes). Healing was assessed via daily slit lamp photos. Tissues were harvested on day 7 and histopathology was performed. Time to complete healing and daily % healing were compared across groups.
Tolerability study revealed that HyStem and HyStem/GSSG were well tolerated, with a trend for faster return to normal histology vs. RL. In the efficacy study, HyStem/GSSG and HyStem/GSSG/rhGH yielded excellent safety and tolerability: histopathology was normal, with no inflammation or angiogenesis. In spite of the small sample size, an efficacy trend was seen with a faster rate to complete defect closure in the HyStem/GSSG/rhGH group as early as Day 5. By Day 6, 80% of eyes with HyStem/GSSG/rhGH were completely healed vs. 50% of HyStem/GSSG vs. 38% of dex alone.
HyStem can deliver, rhGH, such that an efficacy signal for faster corneal wound healing is demonstrated. HyStem and Hystem/GSSG/rhGH were well tolerated in vivo, with normal histopathology. HyStem is a viable polymer to deliver proteins, e.g., rhGH, for corneal defects that have impaired healing.
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