Advanced Drug Delivery Reviews 139 (2019) 92–115 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/addr Cell encapsulation: Overcoming barriers in cell transplantation in diabetes and beyond Marco Farina a,b,1, Jenolyn F. Alexander a,1, Usha Thekkedath a, Mauro Ferrari a, Alessandro Grattoni a,⁎ a Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, United States b Department of Electronics and Telecommunications, Politecnico di Torino, Torino, Italy article info abstract Article history: Cell-based therapy is emerging as a promising strategy for treating a wide range of human diseases, such as di- Received 30 January 2018 abetes, blood disorders, acute liver failure, spinal cord injury, and several types of cancer. Pancreatic islets, Received in revised form 19 March 2018 blood cells, hepatocytes, and stem cells are among the many cell types currently used for this strategy. The encap- Accepted 25 April 2018 sulation of these “therapeutic” cells is under intense investigation to not only prevent immune rejection but also Available online 30 April 2018 provide a controlled and supportive environment so they can function effectively. Some of the advanced encap- Keywords: sulation systems provide active agents to the cells and enable a complete retrieval of the graft in the case of an Cell-based therapy adverse body reaction. Here, we review various encapsulation strategies developed in academic and industrial Encapsulation system settings, including the state-of-the-art technologies in advanced preclinical phases as well as those undergoing Stem cells clinical trials, and assess their advantages and challenges. We also emphasize the importance of stimulus- 3D printing responsive encapsulated cell systems that provide a “smart and live” therapeutic delivery to overcome barriers Pancreatic islets in cell transplantation as well as their use in patients. © 2018 Elsevier B.V. All rights reserved. Contents 1. Cell-basedtherapy............................................................93 2. Celltypes.................................................................94 2.1. Cellsforallogeneicorxenogeneictransplantation...........................................94 2.1.1. Pancreaticislets......................................................94 2.1.2. Myoblasts.........................................................95 2.1.3. Choroidplexus.......................................................96 2.2. Cellsforautologoustransplantation.................................................96 2.2.1. Pancreaticislets......................................................96 2.2.2. Stemcells.........................................................96 2.2.3. Humanembryonicstemcell-derivedbetacells........................................97 2.2.4. Pluripotentstemcells(PSCs)................................................97 2.2.5. Mesenchymalstemcells(MSCs)...............................................97 2.2.6. Adipose-derivedcells....................................................97 2.2.7. Fibroblasts.........................................................97 3. Strategiesforencapsulatedcelltransplantationindiabetes..........................................97 3.1. Encapsulationmaterials.......................................................97 3.2. Microencapsulationsystems.....................................................98 3.2.1. Alginatemicrocapsules...................................................98 3.2.2. Polyethyleneglycol(PEG)coating..............................................99 3.2.3. Agarosemicrocapsules...................................................99 3.2.4. Cellulosemicrocapsules...................................................99 3.3. Microencapsulationindiabetes...................................................99 ⁎ Corresponding author at: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Avenue, R8-111, Houston, TX, 77030, United States. E-mail address: [email protected] (A. Grattoni). 1 Equal contribution. https://doi.org/10.1016/j.addr.2018.04.018 0169-409X/© 2018 Elsevier B.V. All rights reserved. M. Farina et al. / Advanced Drug Delivery Reviews 139 (2019) 92–115 93 3.4. Macroencapsulationsystems................................................... 100 3.4.1. Earlymacroencapsulationstrategiesindiabetes....................................... 101 3.4.2. Currentmacroencapsulationstrategiesindiabetes..................................... 101 4. Celltransplantationbeyonddiabetes................................................... 105 4.1. Chroniceyediseases....................................................... 105 4.2. Neurodegenerativediseases.................................................... 106 4.3. Cancer............................................................. 106 4.4. Woundhealingandregeneration................................................. 107 4.5. Kidneyfailure.......................................................... 107 4.6. Cardiovasculardiseases...................................................... 108 5. Keychallenges............................................................. 108 6. Conclusions.............................................................. 109 Acknowledgements............................................................. 109 References................................................................. 109 1. Cell-based therapy dysregulation of insulin secretion, beta cell apoptosis and self- perpetuating reduction in functional beta cell mass. As a result, exoge- Cell-based therapy consists of implanting or delivering living cells or nous insulin is required to be administered to the patients for survival. sustaining their development in a patient for the treatment of a certain Despite significant advances in the treatment of T1DM, the manage- disease or condition [1]. In contrast to small-molecule drugs and ment of the disease remains suboptimal and is linked to chronic compli- biologics such as engineered proteins and antibodies, which are the cations, comorbidity and mortality even in individuals at a relatively predominant treatment modalities for most diseases, cell-based young age. Whole-pancreas transplantation has shown to prevent therapy delivers complex living entities that are capable of modulating chronic complications and result in adequate glycemic control. How- their functions and sensing and responding to their environment. ever, the invasiveness of the intervention, post-surgical morbidity and The migratory and proliferative capacity and production of cells, the high mortality are still of concern [12–14]. To address the continuous delivery of therapeutics, and the intercellular interactions are some of treatment need for “brittle T1DM” patients, intravascular cell infusion the characteristics that can be manipulated to address the ongoing transplanting allogenic pancreatic islets was developed as a better alter- challenges in various pathologies, including diabetes, cancer, spinal native [15]. cord injuries, and autoimmune and neurodegenerative diseases [2,3]. Pancreatic islet transplantation was first attempted in 1893 [16]. It For example, in the treatment of osteoarthritis, the conventional treat- took 80 years to demonstrate an acceptable rate of success, in the ment comprising opioids and nonsteroidal anti-inflammatory drugs absence of an immune barrier (i.e., using autografts) [17,18]. In the provides pain relief but not the restoration of damaged tissue. By con- 1980s, several autotransplant trials were performed extracting islets trast, cell therapies utilizing induced pluripotent stem cells (iPSCs) or from the patient's own pancreas and infusing them into the liver via autologous chondrocytes repair the damaged cartilage and tissues. the portal vein. Unfortunately, insulin independence was achieved in Transplantation of these cells may thus become a standard treatment only 10% of patients in these early trials [19,20]. The success of this option and is predicted to replace whole organ transplants in certain approach was significantly improved by the development of the Ed- cases, such as in the treatment of diabetes and liver failure [4,5]. monton protocol at the University of Alberta in 2000. In this procedure, The adoption of cells for therapeutic purposes has evolved dramati- Shapiro and colleagues purified pancreatic islets isolated from the pan- cally, beginning with blood transfusions in the 1600s [6], renal trans- creas of a brain-dead donor. Next, using fluoroscopic guidance system to plantation in animal models by Dr. Emerich Ulmannn in 1902 [7,8], guide catheter placement, 4000 islet equivalents per kilogram of the and blood vessel and organ transplantation by Drs. Alexis Carrel and recipient's body weight were infused within the main portal vein. To Charles Guthrie in the early 1900s [9]. Early pioneering developments prevent immune rejection of the transplanted islets, the group devel- in cell transplantation included injections of ox parathyroid cells in oped a glucocorticoid-free immunosuppressive protocol that included human patients in 1931 and lyophilized cells in 1949 by Dr. Paul sirolimus, low-dose tacrolimus, and a monoclonal antibody against the Niehans [10] and the transplantation of islets encapsulated in semiper- interleukin-2 receptor (daclizumab). Although most previous islet meable microcapsules by Dr. Thomas M. S. Chang in 1964 [11]. Today, transplantations have been performed in combination with kidney cell