**Author details**

**4.4. Toward GMP standard**

226 Challenges in Pancreatic Pathology

on the encapsulated islet transplant.

vated B cells) into the nucleus [65].

**5. Conclusion**

survival by preventing diffusion of nutrients and waste.

ive materials to improve islet function and survivability.

One of the key issues facing the engineering of encapsulating material for islet transplantation would be to define standards for the materials. The standards required contain the choice of raw material, the purification method and quality control of the purification, the shape of the device used for encasing the islets, and the quality of the encased islets. The lack of such standards is likely to account for the current variability in the results reported in the literature

As an example of the standard necessary for clinical translation of the encapsulation technology, commercially available alginates used to create islet capsules have been found to contain pathogen-associated molecular patterns (PAMPS). PAMP such as peptidoglycan, lipoteichoic acid, and flagellin among other proteins, endotoxins, and polyphenols [61] can trigger recognition by the innate immune system. PAMPS are recognized by toll-like receptors (TLRs) and pattern-recognition receptors (PRRs) [61, 62], leading to pericapsular fibrotic overgrowth (PFO) [63] as the immune system attempts to isolate the graft. PFO severely hinders graft

In addition to cellular adhesion and PFO, death of encapsulated islets may also be caused by chemokines and cytokines that are small enough to pass through the permeable capsules [64]. TLRs, upon recognition and binding of PAMPS to the receptor surface, initiate an intracellular signaling cascade ultimately resulting in the secretion of a host of inflammatory cytokines attributed to translocation of the NF-κB (nuclear factor kappa-light-chain-enhancer of acti-

Before alginate can be used for clinical transplantation, it will need further development in the GMP manufacturing and purification of the raw materials, to ensure a low amount of PAMP detectable by the recipient's immune system. In addition, the production of the encapsulated islets, including the islet isolation and the encapsulation process, needs to achieve a threshold of standard of quality to ensure a consistent and reliable result, to make it possible

In this chapter, we have covered the variety of options used to protect transplanted islets physically against both transplant rejection and autoimmune assault on β-cells. The technologies covered include the variety of encapsulation devices, materials, and addition of support-

A key step toward translating biomaterial encapsulation of islets toward clinical trial would be to develop a standard of quality that has to be met by the raw encapsulation material, the islets, and the encapsulation process. This will eventually lead to a process that can be scaled up and to adhere to GMP quality requirements. The current variability of results in the literature on encapsulated islet transplants as T1DM treatment can likely be explained by the lack of such standard, making it impossible to reliably compare multiple encapsulation technologies.

to compare the effect of the variety of encapsulation techniques and improvements.

Michael Alexander1 , Huy Nguyen1 , Antonio Flores1 , Shiri Li1, , Paul De Vos<sup>2</sup> , Elliot Botvinick3 and Jonathan Lakey1 \*

\*Address all correspondence to: jlakey@uci.edu

1 Department of Surgery, University of California Irvine, Orange, CA, USA

2 Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands

3 Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
