Self-assembling biomaterials: Liquid crystal phases of cholesteryl oligo(L-lactic acid) and their interactions with cells

Self-assembling biomaterials: Liquid crystal phases of cholesteryl oligo(L-lactic acid) and their interactions with cells
approved May 2, 2002 (received for review December 13, 2001)
Published online before print July 15, 2002
Julia J. Hwang, Subramani N. Iyer, Li-Sheng Li, Randal Claussen, Daniel A. Harrington, and Samuel I. Stupp
PNAS | July 23, 2002
Department of Materials Science and Engineering, Department of Chemistry, Feinberg School of Medicine, Northwestern University, Evanston, IL 60208
Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA,
We report here on the synthesis and characterization of a series of self-assembling biomaterials with molecular features designed to interact with cells and scaffolds for tissue regeneration. The molecules of these materials contain cholesteryl moieties, which have universal affinity for cell membranes, and short chains of lactic acid, a common component of biodegradable tissue engineering matrices. The materials were synthesized in good yields with low polydispersities in the range of 1.05Ò1.15, and their characterization was carried out by small-angle x-ray diffraction, transmission electron microscopy, electron diffraction, differential scanning calorimetry, and atomic force microscopy. These molecular materials form layered structures that can be described as smectic phases and can also order into single-crystal stacks with an orthorhombic unit cell. Their layer spacings range from 58 to 99 ?, corresponding to bilayers of oligomers with an average of 10 and 37 lactic acid residues, respectively. The self-organized layered structures were found to promote improved fibroblast adhesion and spreading, although the specific mechanism for this observed response remains unknown. The ability of self-assembling materials to present ordered and periodic bulk structures to cells could be a useful strategy in tissue engineering.
Abbreviations: PLA, poly(L-lactic acid); C-LA, cholesteryl-(L-lactic acid); SAXS, small-angle x-ray scattering; DSC, differential scanning calorimetry; TEM, transmission electron microscopy; AFM, atomic force microscopy; DHE, dehydroergosterol
Self-assembly strategies could bring novel capabilities to biomaterials used in advanced medicine and biotechnology. In a self-assembly strategy, a specific thermodynamically stable structure is targeted by design of specific molecules. The past decade has seen a great deal of progress in such strategies, including contributions from our laboratory (1Ò3). Self assembly of biomaterials would be particularly useful in medicine, because the formation of targeted structures could be programmed to occur on contact with tissues. Additionally, the control of three-dimensional structure can target the spatial presentation of bioactive ligands to impact directly the behavior of cells. Such control could impact a material's ability to promote cell division, differentiation, and synthesis of extracellular matrix. Self-assembling biomaterials could also be used to design with greater precision molecular delivery to cells. In this paper, we report on the design and synthesis of a novel family of self-assembling biocompatible structures by using cholesterol as a mesogen, intended to initiate the investigation of this general class of biomaterials.
The molecules of the model system studied here contain cholesterol moieties and short chains of oligo-(L-lactic acid) connected through an ester bond. Kricheldorf and Kreiser-Saunders (4) prepared by a similar methodology a series of poly(L-lactic acid) (PLA) molecules, end-functionalized with various vitamins, hormones, and drugs. Cholesterol moieties were selected in the molecular design of our system for several reasons. One is the thermodynamic affinity of cholesterol for cell membranes and its ability to change their properties, for example enhance their mechanical durability and decrease passive permeability (5Ò8). Also, cholesterol is an important component in the membranes of eukaryotic cells, and its homeostasis is critical to cell survival. Recent reports (9, 10) point to the importance of cholesterol in stabilizing membrane rafts containing receptors and describe the complex pathways for its biosynthesis, efflux, uptake, and trafficking. Very recently, a bioactive role for cholesterol has also been identified in the central nervous system, where its production by glial cells promotes improved synaptogenesis by surrounding neurons (11). We therefore thought that an anchoring biomaterial that could supply a universally fundamental molecule to mammalian cells would be an attractive substrate for cell attachment and proliferation.
Cholesterol was also selected because of the well known mesogenic nature of cholesterol and its derivatives, that is, their ability to self order into liquid crystalline substances (12, 13). Liquid crystalline matter was in fact discovered over a century ago by using cholesterol derivatives (12). As part of our system's design, oligoester chains of L-lactic acid and cholesterol are both considered to be easily biodegradable, thus making the system suitable for the preparation of tissue engineering templates that sustain cell proliferation and migration. Finally, higher molecular weight PLA is a common matrix material in tissue engineering scaffolds (14Ò19), and therefore the cocrystallization or secondary bonding of molecules studied here could easily occur on its surface. In this way, the self-assembling structures could be used to modify the internal surfaces of three-dimensional scaffolds fabricated from lactic acid or its copolymers with glycolic acid.
In this paper, we discuss the synthesis and characterization of various cholesteryl-(L-lactic acid) (C-LA) materials. The structural characterization has been carried out primarily through small-angle x-ray scattering (SAXS), optical microscopy, differential scanning calorimetry (DSC), transmission electron microscopy (TEM), electron diffraction, and atomic force microscopy (AFM). We then describe our initial studies on culturing of mouse fibroblasts on these novel biomaterials.
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