3D cell-laden polymers to release bioactive products in the eye
Introduction
The loss of vision, culminating in blindness, is one of the most prevalent and feared health conditions any person will ever face. According to the World Health Organization (2016) approximately 180 million people worldwide have visual impairments secondary to ophthalmic disease. Some of the most devastating examples are age-related progressive diseases of the posterior segment of the eye including age-related macular degeneration (AMD), diabetic macular edema (DME), retinitis pigmentosa (RP) and diabetic retinopathy. These diseases impact tens of millions of people leading to vision impairment and blindness, reduced independence and limited normal activities. In developed nations, these diseases are the leading causes of vision loss. The societal and economic burden of these diseases is staggering. In the United States alone it has been estimated that >40% of the population has some type of disease causing impaired vision with an annual economic impact of $35 billion USD (National Center for Health Statistics, 2012).
While recent advances in biology are shedding light on the underlying nature of ocular diseases and have led to some new symptomatic treatments there are no cures or prosthetics that restore vision and the best hopes for patients is a slowing of disease progression. Unfortunately, the need for new and innovative approaches us becoming increasingly urgent as the aged population increases. While numerous factors contribute to the lack of therapeutics including limited understanding of disease mechanisms, significant patient heterogeneity, and our limited ability to detect early stage disease; much of the difficulty in treating and managing these diseases results from the unique anatomy and physiology of the eye that consists of a multilayered system that protects it from dangerous substances, microorganisms and toxins. These barriers, which are essential for maintaining vision, also limit the entry of potentially therapeutic drugs to the eye (Urtti, 2006). These barriers begin with the corneal and conjunctival epithelial layers that cover the ocular surface. The blood–aqueous barrier, consisting of the uveal capillary endothelia and ciliary epithelia, limits systemically administered drug access to the anterior segment, while the blood–retina barrier limits distribution from the circulating blood to the retina and vice versa. Two additional components of this system include the outer and inner blood–retina barriers that are formed by the retinal pigment epithelium (RPE) and the tight retinal capillary walls, respectively.
Traditional routes of drug delivery to the eye include topical, oral, intravitreal and periocular delivery (Box 1). Topical application is well-suited for short-term delivery of drug solutions, suspensions or ointments but access beyond the anterior segment of the eye is limited (Lakhani et al., 2018). Systemic dosing using oral or intravenous delivery can be used to deliver drugs to the retina but this route suffers from several issues including peripheral metabolism/degradation, limited ability to cross the inner and outer blood-retinal barriers, and the need to use very high systemic doses which carry significant systemic toxicological potential (Awwad et al., 2017). Delivery of potential therapeutic proteins is further hampered by protein degradation and aggregation significantly limiting sustained delivery across these barriers (Awwad et al., 2017).
Periocular injection can enable drug delivery to the posterior segment by crossing the sclera, via the choroidal systemic circulation, or through the aqueous and vitreous humor (Waite et al., 2017). Direct intravitreal delivery provides the highest drug bioavailability to the retina because of the close association of the vitreous and retina but repeated intravitreal injections can lead to retinal hemorrhage/detachment, endophthalmitis and cataracts. Drug washout and clearance is also significant with these routes making sustained, long-term delivery in chronic diseases even more difficult to achieve (Martin, 2018). While difficult to accomplish, the value of sustained delivery is confirmed by the long-term drug delivery and efficacy achieved using the Retisert and Iluvian implant systems to deliver fluocinolone (Bertens et al., 2018).
This review focuses on an emerging concept for long-term drug delivery based on the use of living cells that are encapsulated within small, implantable capsules in the form of spheres or slender hollow fibers. Encapsulated cell therapy overcomes many of the fundamental obstacles of traditional approaches by combining the potency of de novo in situ synthesis of cell-derived molecules (including proteins and peptides) with the safety of an implantable and retrievable medical device. In this approach, cells are enclosed or “encapsulated” within a capsule that has a semipermeable outer wall or membrane that can be implanted directly into the desired region. The capsule wall morphology provides a pore structure that allows oxygen and nutrients to enter and nourish the cells while simultaneously providing a route for cell-secreted proteins, small molecules, antibodies, etc. to diffuse from the capsule and into the surrounding environment. Encapsulated cell systems have been used for many years to deliver molecules both systemically and into compartmentalized segments of the body including the brain and eye. While thousands of pre-clinical studies have confirmed the potential of this approach in multiple disease models, recent clinical studies have further demonstrated the clinical and medical translational reality of encapsulated cell technology. Within the visual system, locally implanted cells provide long-term release of potent drugs, proteins and peptides to specific areas including the vitreous or directly to the choroid, RPE, ganglion cells or photoreceptors of the neural retina. Here, we detail progress using these systems in both preclinical models and human diseases of visual impairment with an “eye” towards scaled and widespread clinical application.
Section snippets
The immune privilege of the eye provides an opportunity for cell therapy
The eye has a unique immunological privilege (Jiang et al., 1993). The limited exchange between the systemic system and the ocular environment restricts the entry of blood-borne factors and cells into the various chambers of the eye. From an evolutionary perspective, this immune privilege has developed to limit and control the intraocular expression of immunogenic inflammation which, if uncontrolled, could lead to serious functional and survival limitations. The immune privilege of the eye is
A brief history of encapsulated cell therapy
In the 1960's T.M.S. Chang introduced the concept of encapsulation as a strategy for immunoprotection of transplanted cells and tissues (Chang, 1964). This strategy, dubbed “artificial cells”, incorporated the cells into spherical polymeric structures designed to ensure maximum surface/volume ratio and optimum protection. As originally conceived, cells are included in biocompatible polymeric matrices that allow the ingress of nutrients and oxygen diffusion to the encapsulated cells together
Micro-versus macroencapsulation
Two general types of devices are used for the immobilization of cells: microcapsules and macrocapsules. The latter, most frequently designed as hollow fibers, are composed of a semipermeable polymer that surrounds the encapsulated cells. Its size can range from a few millimeters to a few centimeters. In contrast, microcapsules are typically 100 to 700 μm in diameter. In microcapsules, the cells are incorporated into spherical polymer matrices coated with a semipermeable membrane that increases
Most relevant properties of encapsulation devices
The ultimate and ideal drug delivery system should provide an effective concentration of the therapeutic compound at the target site for an extended period of time; all while minimizing systemic exposure. At the same time, the success of a biomaterial-based, implantable drug delivery system is highly dependent on the capacity to customize and tune its building-blocks to achieve appropriate biocompatibility, physicochemical properties and desired biological responses. The chemical composition,
Delivery of neurotrophic and anti-angiogenic proteins
Neurotrophic factors play key roles in the repair and protection of normal neuronal function in adult organisms and in the survival and differentiation of neurons during development, following brain injury, and in neurodegenerative diseases (Skinner et al., 2009). Several trophic signaling molecules provide neuroprotection to retinal neurons in vivo and in vitro including basic fibroblast growth factor (bFGF), neurotrophic cytokines, nerve growth factor (NGF) and brain-derived neurotrophic
Room for progress
Significant progress has been achieved in the delivery of potential therapeutics to the eye and cell encapsulated-based protein delivery is one of the more promising approaches with notable demonstrations of long-term and reasonably stable protein delivery both in pre-clinical and clinical studies. Still, there are critical issues that need to be overcome to optimize use of this therapeutic approach. First, while device-related adverse events have been uncommon to date, more detailed studies
Conclusion and future directions
Retinal diseases such as macular degeneration, diabetic macular edema, retinitis pigmentosa, glaucoma and macular telangiectasia are extremely common and each of them presents a unique etiological and pathological spectrum. This heterogeneity has played a limiting factor in the development of novel therapeutics. Another major limiting factor has been the development of drug delivery systems capable of providing sustained, long-term delivery to the posterior segment of the eye via the
Conflicts of interest
Authors declare no conflict of interests.
Acknowledgements
The authors wish to thank projects SAF2016-76150-R from the Spanish Ministry of Economy, Industry and Competitiveness and PRGF 3.0 ELKARTEK KK-2017/00063 from the Basque Country Government and intellectual and technical assistance from the ICTS “NANBIOSIS”, more specifically by the Drug Formulation Unit (U10) of the CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN) at the University of the Basque Country (UPV/EHU). We also appreciate the support from the Basque Country Government
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Percentage of work contributed by each author in the production of the manuscript is as follows: Gorka Orive 35%; Dwaine Emerich 20%; Edorta Santos 20%; Rosa Hernandez 20%; JL Pedraz 20%; Julia E. Vela Ramirez 15%; Alireza Dolatshahi-Pirouz 15%; Nicholas A. Peppas 15%; Ali Khademhosseini 10%.