Elsevier

Biomaterials

Volume 24, Issue 20, September 2003, Pages 3493-3503
Biomaterials

Synthesis, permeability and biocompatibility of tricomponent membranes containing polyethylene glycol, polydimethylsiloxane and polypentamethylcyclopentasiloxane domains

https://doi.org/10.1016/S0142-9612(03)00189-3Get rights and content

Abstract

The synthesis of “smart” tricomponent amphiphilic membranes containing poly(ethylene glycol) (PEG), polydimethylsiloxane (PDMS) and polypentamethylcyclopentasiloxane (PD5) domains is described. Contact angle hysteresis indicates that in air, the surfaces of such PEG/PD5/PDMS membranes are enriched by the hydrophobic components, PDMS and PD5, while in water, the surfaces are rich in the hydrophilic PEG. The oxygen permeability of a series of membranes with varying Mc,hydrophilic (Mn,PEG=4600, 10,000 and 20,000 g/mol) and varying PEG/PD5/PDMS compositions was studied. Oxygen permeability increased with the amount of PDMS in the membrane. The molecular weight cut-off (MWCO) ranges and permeability coefficients of insulin through a series of PEG/PD5/PDMS(=29/14/57) membranes with varying Mc,hydrophilic were determined. Insulin permeability is directly related to Mc,hydrophilic of the membrane. MWCO studies show that the membranes are semipermeable to, i.e., allow the transport of smaller proteins such as insulin (Mn=5733 g/mol, Rs=1.34 nm) and cytochrome c (Mn=12,400 g/mol, Rs=1.63 nm), but are barriers to larger proteins such as albumin (Mn=66,000 g/mol, Rs=3.62 nm). Implantation of representative membranes in rats showed them to be biocompatible. According to these studies, PEG/PD5/PDMS membranes may be suitable for biological applications, e.g., immunoisolation of cells.

Introduction

Recently, we described the first synthesis of unique tricomponent poly(ethylene glycol) (PEG)/polypentamethylcyclopentasiloxane (PD5)/polydimethylsiloxane (PDMS) hydrogel membranes designed for biomaterials applications [1], [2], i.e., macroencapsulation, immunoisolation. The PEG domains of these membranes provide for diffusion of aqueous solutions, the PDMS domains provide high oxygen permeability and desirable mechanical properties, and the PD5 domains provide crosslinking and reinforcement of the linear PEG and PDMS segments plus additional oxygen permeability. We are continuing these investigations with the objective of creating strong thin implantable/explantable biocompatible PEG/PD5/PDMS membranes with controlled pore sizes designed for maximum permeability to oxygen and low molecular weight proteins.

The present communication confirms and extends our earlier reports [1], [2] and, specifically, describes the synthesis of a series of various composition PEG/PD5/PDMS membranes designed to provide rapid oxygen and insulin transport, and permselectivity. Further, we demonstrate by contact angle measurements the reorganization of membrane surfaces when it comes in contact with various media, and study the transport of various molecular weight proteins through our constructs. We also demonstrate by in vivo implantation experiments in rats the biocompatibility of our membranes.

Section snippets

Symbolism used

The membranes are identified by their chemical constituents: PEG, PD5, PDMS, and by the Mn×10−3 of the two linear components (PEG and PDMS) in the subscript. The Mn of the PD5 is unknown and therefore is not indicated. The symbols first show the hydrophilic component, PEG, followed by the crosslinker, PD5, and finally the hydrophobic component, PDMS. For example, PEG(4.6)/PD5/PDMS(28.5) stands for a network consisting of a PEG block of Mn=4600 g/mol, and a PDMS block of Mn=28,500 g/mol

Materials

The source and purity of the chemicals used for the synthesis of membranes have been described [1]. Reagents and solvents were from Aldrich or Fisher. Karstedt's catalyst (Pt with 1,3-divinyltetramethyldisiloxane in xylene solution), vinyl-ditelechelic polydimethylsiloxane (V-PDMS-V) reinforced with 18–20% fumed silica, and pentamethylcyclopentasiloxane (D5H) were all obtained from Gelest Chemicals, and were used as received. The synthesis of allyl-ditelechelic poly(ethylene glycol) (A-PEG-A)

Oxygen permeability

The details of the techniques and the scheme of the apparatus developed for the study of oxygen permeability have been described [2]. The permeability and initial oxygen permeability rates (i.e., flux) through representative tricomponent membranes were calculated from diffusion data collected at regular intervals over a period of 8 h at 24°C. Various authors use various units to report oxygen permeability. We calculated oxygen permeability (P) in barrers [9] by the following equation:P=DK=QLAtΔP

Biocompatibility studies

In vivo biocompatibility experiments were performed on Lewis strain male rats (220–235 g) (Harlan Sprague Dawley). Medical grade PTFE tube Goretex and non-medical grade butyl rubber were also implanted for comparison. Neutral buffered formalin solution (10%), Hematoxylin and Eosin, ketamine/aceptrozamine (KXA) anesthetic, atropine SA, butyl barbital (‘fatal plus’), rubbing alcohol, iodine, and xylene were obtained from the NorthEastern Ohio Universities College of Medicine (NEOUCOM) animal

Histology

Thin sections of the explanted membranes and surrounding tissue were prepared. To facilitate dehydration, the samples were automatically passed through 70%, 80%, 95%, and 100% alcohol solutions. Xylene was used for clearing. The samples were then infiltrated with and embedded in paraffin. With a microtome, 4 μm sections were cut from the paraffin blocks. The thin sections were mounted on glass slides, the slides were deparaffinized in xylene and alcohols graded from 100% to 70%, rehydrated in

Synthesis and overall membrane composition

Scheme 1 helps to visualize the overall strategy used for the preparation of tricomponent membranes and the microarchitecture of the constructs. The synthesis starts with random cohydrosilation by D5H of A-PEG-A and V-PDMS-V catalyzed by Karstedt catalyst and yields PEG and PDMS chains attached to D5H units. The relative concentration of the functional groups in the charge (i.e., allyl, SiH and vinyl) determines the rate of network formation. Membranes can be prepared with charges in which the

Oxygen diffusion

Oxygen permeation through our membranes is of great interest because of their intended use in macroencapsulation devices. Hypoxia of encapsulated cells is usually the Achilles heal of immunoisolation [16]. Our intention was to create robust membranes with the highest possible oxygen permeability. Indeed, the components of our networks were selected with oxygen permeability in mind: PDMS was selected as the hydrophobic component because of its unique combination of properties including

Biocompatibility/histological assessment

The biocompatibility and immunocompatibility of polymers are of crucial importance if they are to be used for implantable devices. The components of tricomponent membranes were selected for their demonstrated compatibility with vertebrate hosts [23]. Many research groups have studied the biocompatibility of PEG [24]. For example, Irvine et al. [25] studied protein resistance of linear and star-shaped PEG for biomaterials. Bicomponent membranes of polyisobutylene/polydimethyl siloxane [26] and

Conclusions

A series of novel tricomponent PEG/PD5/PDMS membranes with varying compositions and Mc,hydrophilic was synthesized. Contact angle measurements showed that the hydrophobic (PDMS and PD5) and hydrophilic (PEG) domains were undergoing rapid reversible reorganization, based on the exposure of the surface to a hydrophobic (air) or hydrophilic (water) environment. The oxygen permeability (DK) and flux (μl of oxygen/area/time) of these membranes increase with the increasing amount of PDMS. The insulin

Acknowledgements

Financial support by the National Science Foundation (grant DMR-99-88808 and 0243314) is gratefully acknowledged. We thank Dr. Walter Horne and members of the Clinical Medicine Unit at NEOUCOM, and Dr. Neena Goel of the Department of Microbiology & Immunology at NEOUCOM for protocols and procedures for the biocompatibility studies, and Dr. Andras Nagy of Royal Sheen Co. for help with contact angle measurements.

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