Bernards Daniel A, Ma Chu Jian, Zhang Youning, Rodriguez Tannia M, Dickson John, Kharbikar Bhushan N, Bhisitkul Robert B, Desai Tejal A
University of California, San Francisco, Department of Bioengineering and Therapeutic Sciences, San Francisco, California 94143, United States.
University of California, San Francisco, Department of Ophthalmology, San Francisco, California 94143, United States.
ACS Mater Au. 2023 Mar 13;3(3):255-264. doi: 10.1021/acsmaterialsau.3c00004. eCollection 2023 May 10.
Sustained delivery of protein therapeutics remains a largely unsolved problem across anatomic locations. Miniaturized devices that can provide sustained delivery of protein formulations have the potential to address this challenge via minimally invasive administration. In particular, methodologies that can optimize protein formulation independent of device manufacture have the greatest potential to provide a platform suitable for wide applications. The techniques developed here demonstrate the fabrication of tubular devices for sustained release of protein therapeutics. Utilizing a dip-casting process, fine-scale tubes can be reliably produced with wall thickness down to 30 μm. Techniques were developed that enabled effective loading of either solid or liquid formulations, while maintaining a cylindrical form-factor compatible with placement in a 22-gauge needle. Further, highly compacted protein pellets that approach the expected density of the raw materials were produced with a diameter (∼300 μm) suitable for miniaturized devices. Release from a solid-loaded device was capable of sustaining release of a model protein in excess of 400 days. Given significant interest in ocular applications, intravitreal injection was demonstrated in a rabbit model with these devices. In addition, to simulate repeated injections in ocular applications, serial intravitreal injection of two devices in a rabbit model demonstrated acceptable ocular safety without significant intraocular inflammation from clinical exam and histology.
蛋白质治疗药物的持续递送在各个解剖部位仍然是一个基本未解决的问题。能够实现蛋白质制剂持续递送的小型化装置有潜力通过微创给药来应对这一挑战。特别是，能够独立于装置制造来优化蛋白质制剂的方法，最有潜力提供一个适用于广泛应用的平台。此处开发的技术展示了用于蛋白质治疗药物持续释放的管状装置的制造。利用浸铸工艺，可以可靠地生产出壁厚低至30μm的精细尺度的管子。开发的技术能够有效地装载固体或液体制剂，同时保持与22号针头放置兼容的圆柱形外形。此外，还生产出了高度压实的蛋白质微丸，其直径（约300μm）适合小型化装置，且接近原材料的预期密度。固体装载装置能够使模型蛋白质持续释放超过400天。鉴于对眼部应用的浓厚兴趣，在兔模型中展示了使用这些装置进行玻璃体内注射。此外，为了模拟眼部应用中的重复注射，在兔模型中对两个装置进行连续玻璃体内注射，临床检查和组织学结果显示眼部安全性可接受，且无明显眼内炎症。
