Cell microencapsulation technologies for sustained drug delivery: Clinical trials and companies

Highlights

• Alginate-containing device's biocompatibility has notably improved in recent years.

• The use of stem cells has opened a new world of possibilities for these technologies.

• Decades of pre-clinical work in academia is now being transferred to novel startups.

• Some of the described devices are already being tested in clinical trials.

• Target pathologies include diabetes, cancer or lysosomal diseases, among others.

In recent years, cell microencapsulation technology has advanced, mainly driven by recent developments in the use of stem cells or the optimization of biomaterials. Old challenges have been addressed from new perspectives, and systems developed and improved for decades are now being transferred to the market by novel start-ups and consolidated companies. These products are mainly intended for the treatment of diabetes mellitus (DM), but also cancer, central nervous system (CNS) disorders or lysosomal diseases, among others. In this review, we analyze the results obtained in clinical trials to date and define the global key players that will lead the cell microencapsulation market to bring this technology to the clinic in the future.

Introduction

Experts estimate that the market of cell encapsulation technologies, with a current value of ∼US$250 million, will reach a value of ∼US$303 million by 2024 [1]. Several key areas are included in this market, such as regenerative medicine, cell transplants, and encapsulation of probiotics or controlled-release medication.

The growth of the market results mainly from increases in the incidence of several of the target diseases of these therapies, the advances in, and improved knowledge of, the technologies, the increase in both private and public investments, and the acceptance and understanding of these possible therapies by society. However, the high manufacturing costs, limited availability of high-quality raw materials, and the existence, in some cases, of alternative therapies, are expected to contain such growth in the coming years.

Among the applications related to cell encapsulation, the sustained release of drugs is the one that currently produces the greatest benefits. Moreover, this trend is expected to continue, mainly because of the latest technological advances and the use of increasingly biocompatible and affordable materials. In fact, three of the five most influential companies in the field of cell encapsulation today [Viacyte, Inc., Neurotech Pharmaceuticals, Inc., and Living Cell Technologies Ltd. (LCT)] focus their efforts on developing systems for the sustained release of therapeutic molecules from live encapsulated cells.

In these systems, cells producing molecules of therapeutic interest are immobilized in biocompatible materials that are usually surrounded by a semipermeable polymeric membrane. The capsule prevents the passage of high-molecular-weight molecules, such as antibodies and other agents of the immune system, protecting the cells from the immune response of the host, while allowing the release of the therapeutic molecule of interest. In this way, different sustained-release profiles of the therapeutic molecule, synthesized de novo, can be obtained without the need for immunosuppressive treatments, thus avoiding some of the adverse events associated with transplantation of cells and organs [2]. Traditionally, the market is divided between devices considered ‘micro’ and ‘macro’.

Cell macroencapsulation systems are systems in which the cells are located in relatively large diffusion chambers with semipermeable properties. These devices can have different shapes, such as discs, flat sheets, or hollow fibers. The application of cell macroencapsulation devices has shown good results in vivo, demonstrating an undeniable therapeutic potential [3]. However, macrocapsules are characterized by a relatively small surface:volume ratio, which is probably their worst disadvantage. This implies the need for large amounts of nutrients and oxygen to achieve adequate diffusion into the chamber and limits the number of cells that can be encapsulated without creating necrotic nuclei in the innermost and inaccessible areas. However, they also have the advantage of allowing the implant to be removed easily in the event of adverse effects or loss of function.

By contrast, cell microencapsulation, comprising spherical particles between ∼100 and 1500 μm in diameter, represents an interesting alternative, improving the surface:volume ratio and increasing the diffusion of nutrients and oxygen inside the capsules. Both natural and synthetic polymers have been tested for cell microencapsulation technologies 4, 5, 6. Among natural polymers, polysaccharides are the most widely used, probably because they allow relatively mild encapsulation processes that are compatible with cell viability. In addition, most polysaccharides are capable of forming hydrogels [7], with a high water content and hydrophilic nature and, therefore, high biocompatibility. Examples of natural polymers are alginate, agarose, collagen, or cellulose [5]. By contrast, polyethylene glycol (PEG) continues to be the most widely used option among synthetic polymers, along with poly(lactic-co-glycolic acid) (PLGA) and polyvinyl alcohol (PVA) [6].

Among the abovementioned materials, alginate is by far the most widely used. This polysaccharide allows relatively smooth encapsulation processes, going from sol to gel when it reacts with divalent ions, such as Ca²⁺ and Ba²⁺, and forming hydrogels with a high water content and biocompatibility [8]. The hydrogel matrices are typically reinforced by means of polycation-based coatings, which provide the microcapsule with enhanced mechanical properties and more controlled permeability.

Another interesting example that has also been tested in clinical trials are the cellulose sulfate microcapsules [9], which show appropriate physical-mechanical properties for cell encapsulation purposes. In this case, the sodium cellulose sulfate (NaCS) solution that forms the capsule core serves as the polyanion and the precipitation bath of poly(diallyldimethylammonium chloride) (PDADMAC) as the polycation for the polyelectrolyte complex layer formation at the surface of the droplets, thus forming the capsules by covering the droplets with a solid semipermeable membrane [10].

The first in vivo studies with microencapsulated cells, in this case pancreatic islets, were already carried out by Lim and Sum during the 1980s [11], and during the following decades, type 1 DM (T1DM) has persisted as the main target pathology. However, this versatile strategy has also been used for applications as diverse as myocardial regeneration, anemia, liver pathologies, different cancer types, and neurodegenerative diseases, or as a therapeutic alternative in severe hypoparathyroidism [12]. Nevertheless, its clinical application has remained elusive mainly because of biocompatibility issues that usually lead to fibrosis and implant failure.

In recent years, driven by advances in related disciplines, old challenges have been addressed from new perspectives, taking cell microencapsulation technology one step further. On the one hand, some groups have focused their efforts on optimizing the purification protocols of the alginate 13, 14, 15 to eliminate the endotoxins, proteins, and polyphenols that trigger immune responses and that are key factors in implant viability. On the other hand, chemical modifications of the alginates are proving to be a promising option to reduce the immunological reactions against the implant 16, 17, 18. Triazole-containing alginate analogs, identified by Vegas et al., are a representative example of the latter, because they have demonstrated to significantly reduce foreign body response, inhibiting macrophage recognition and fibrosis formation 16, 17, 19. Moreover, recently Veiseh et al. [20] suggested that the size of the microcapsules is a determinant factor for implant biocompatibility, although this conclusion generated debate in the field [15].

The selected cell type differs depending on the target pathology. In some cases, working with allogeneic or xenogeneic primary cells might be the safest option, exploiting the natural productive capacity of the selected cell type. However, the sources of allogenic cells are usually limited and using nonhuman cells is normally associated with stronger immunological reactions against the implant, related to xenogeneic epitopes. In recent years, the possibility of obtaining the desired cell type from human pluripotent stem cells (hPSCs), either embryonic stem cells (hESCs) or induced PSCs (iPSC), has opened a previously unthinkable world of possibilities, which are already being explored, with promising results 19, 21, 22, 23, 24.