Review Cell microencapsulation technology : Towards clinical applications

Authors: Ainhoa Murua, Aitziber Portero et al, 2008 Journal of Controlled Release Journal homepage: www.elsevier.com/locate/jconrel Presented by: Oscar Leonardo Mosquera Electronic Engineer

Outline

Introduction Cell encapsulation technology Biomaterials Requirements of the technology The versatility of cell encapsulation technology Concluding remarks. Future directions and challenges.

Introduction
Release the therapeutically active molecule at the level and dose it is needesd and during the optimal time Delivery process Pharmacokinetics properties

Cell uencapsulation Based on Immobilization of cells, polymeric matrix, Semipermeable membrane Long-term release of therapeutics Versatility Delivery of drugs via Intravascular, subcutaneous Pulmonary, ophtalmic, And oral routes Diabetes, cancer, CNS Diseases and endocrinology Disorders among others Encapsulated cells Are isolated from the Host immune system Exchange of nutrients

Ideal system: - achieve an effective drug Concentration at the target Tissue for an extended Period of time. -minimize systemic exposure -Provide tight control over the Device in case of side-effects

Cell encapsulation technology

Difussion of Nutrients Delivery for a longer Time as cell release The products continously Immobilization of cells Within a semipermeable membrane u-encapsulation of cells Instead of therapeutics products Immobilization of cells Shows important Advantages Sustained and Controlled Delivery of de novo More Phisiological concentrations If cells manage to exit the device hosts immune System might attack
protection

-Mechanical stress -hosts immune system Reduction or even lack of Administration of immunosuppresants

Transplantation of non human cells

Genetically modified cells

If the device Is borken? Toxicity by a quick delivery of high [drug] could be avoided

Cells release the products continously

Express any desired protein unmodify host genome

A. Murua et al. / Journal of Controlled Release 132 (2008) 7683

Biomaterials

Alignates are linear unbranched polymers containing linked D-mamuronic acid (M) and L-guloronic acid (G)

Many different materials are employed to encapsulate cells, among them, alignates are nowadays the most studied and characterized for cell encapsulation technology

Alignates create 3D structures when they react with multivalent ions. Divalent cations such as calcium bind between adjacent alignate chains (G-blocks) creating interchain bridges which cause gelling of the aqueous alignate solution

U-capsules can be formulated by many different methods, the most often described system is based on an alignate core surrounded by a polycation layer which at the same time is covered by an outer alignate membrane. (the polycation forms a semipermeable membrane, which improbes the stability and biocompatibility of the u-capsule.) Different polycation suc as, poly-l-lysine (PLL), poly-l-ornithine (PLO), chitosan, among others have been employed to cover the alignate matrix Although capsules with alternatives materials have been developed, in vitro studies have not proven to be better and few in vivo data are available.

Table 1. Cell encapsulation approaches based on alignate matrices.

Requirements of the technology

Optimization process to Come closer to a realistic Proposal for clinical app.

Biocompatibility Monitor and remove All its contaminant (endotoxins, certain Proteins ) Commercially Ultrapure aligates have Been found to contain Residual proteins (J.Dusseault et al, 2006 S.K.Tom et al, 2006 G.Orive et al, 2006) Loss of 2-10% of capsule Due to macrophages

Optimal delivery site Immune response Against capsules Implanted IP was More severe than SC And KC cases

Other issues Monitor the Implanted device Alignate-based Radiopaque X-ray monitoring (B.P.Barnett et al 2006) Cell viability and capsule Permeability were not affected But the metals employed are Toxic both for the encapsulated Cells and the recipient -Barium sulfate -Orbismuth sulfate

The versatility of cell encapsulation

Many disease are closely tied with deficient or subnormal metabolic and secretory cell functions (Parkinson disease, Diabetes mellitus, hepatic failure) It is often extremely complicated or even impossible to mimic the moment-to-moment precise regulation and the complex role of the hormone, factor, or enzyme that is not produced by the body. A suitable election of the cells holds the key to the succes of any biomedical application :

Bioorgans: primary cells ( i.e, hepatic islet) Living drug factories: genetically modified cells Stem cell technology

Concluding remarks

With continuing advances in genetics, materials science, pharmaceutical technology, biology and chemical engineering, improvements will lead to progression in this therapeutic approach which may become one day closer to a realistic proposal for clinical application. Due to the major advantages that cell encapsulation offers as a living drug delivery system, it can be expected that its practical importance will continue to steadily increase in the future.