Elsevier

Biomaterials

Volume 26, Issue 22, August 2005, Pages 4495-4506
Biomaterials

Degradable thiol-acrylate photopolymers: polymerization and degradation behavior of an in situ forming biomaterial

https://doi.org/10.1016/j.biomaterials.2004.11.046Get rights and content

Abstract

Degradable thiol-acrylate photopolymers are a new class of biomaterials capable of rapidly polymerizing under physiological conditions upon exposure to UV light, with or without added photoinitiators, and to depths exceeding 10 cm. These materials are formed in situ, and the versatility of their chemistry affords a high degree of control over the final material properties. For example, variations in monomer mole fractions directly affect the final network molecular structure, varying the time required to achieve complete mass loss from 25 to 100 days, the molecular weight distributions of the degradation products, and the swelling ratios and compressive moduli throughout degradation. Additionally, varying the mole fraction of multifunctional thiol monomer in the initial reaction mixture controls the concentration of reactive sites in the network available for post-polymerization modification of the polymer.

Introduction

There is an emerging interest in the development of in situ forming biomaterials for tissue engineering and drug delivery applications. Various mechanisms for forming these materials have been investigated, including ionic crosslinking of alginate [1], thermally induced physical crosslinking of pluronics [2] and poly(N-isopropylacrylamide-co-acrylic acid) [3], and enzymatic or pH-induced gelation of chitosan [4]. These and a variety of other formation mechanisms all share the common goal of creating biocompatible, chemically versatile materials capable of maintaining sustained, localized drug delivery or acting as a scaffold for cell encapsulation or seeding [5]. Unfortunately, most of these methodologies and materials also have limited control of the gelation kinetics and material properties. In contrast, covalently crosslinked materials dramatically improve control of the crosslinking density, which subsequently impacts polymer diffusivity and permeability, degradation rate, equilibrium water content, elasticity, and modulus [6], providing materials that can be tailored to more closely mimic the mechanical properties of native tissues.

Extensive research into covalently crosslinked, degradable biomaterial networks has occurred in the past 25 years. Three main polymerization mechanisms are used to form covalently crosslinked polymeric biomaterials, including chain-growth, step-growth, and mixed-mode chain and step growth mechanisms. During formation of a typical chain-growth network, active centers rapidly propagate through monomers containing multiple carbon–carbon double bonds to form high-molecular-weight kinetic chains that are covalently crosslinked (Fig. 1a). The initiating species in these chain-growth systems, typically radicals, are generated by a variety of methods including thermal energy [7], redox reactions [8], and cleavage of a photoinitiator molecule when irradiated with UV or visible light [5], [9]. Photopolymerizations have the added benefit of spatial and temporal control of the polymerization simply through controlling when and where the sample is exposed to the initiating light source. Degradation is incorporated into covalently crosslinked networks through inclusion of hydrolytically cleavable anhydride or ester groups [10], [11], [12], [13], or enzymatically cleavable peptide linkages [14], [15], [16], [17] in the crosslink segments. For each type of degradable network, the degradation products are comprised of the original monomer core from the starting materials, individual repeat units from the degradable segments, and the high-molecular-weight kinetic chains generated during polymerization (Fig. 1a).

Modifications to the monomer core-chemistry in chain-growth networks directly impact the network's crosslinks and allows degradation behavior, modulus, elasticity, and equilibrium swelling ratios to be tailored [18], [19], [20]. For example, highly crosslinked networks formed from low-molecular-weight, hydrophobic dimethacrylated polyanhydrides degrade through a surface erosion mechanism while moderately crosslinked hydrogels formed from high-molecular-weight, hydrophilic dimethacrylated poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) undergo bulk erosion [21], [22], [23]. Another example is the ability to tailor the mechanical strength and modulus of oligo(poly(ethylene glycol) fumarate) hydrogels through modifications of the PEG molecular weight [24], crosslinker mole fraction [25], and porogen content [26].

Despite the demonstrated advantages of these polymeric networks, the broader utility of degradable chain-growth biomaterials is limited by several factors. First, only the crosslink segments degrade, leaving high-molecular-weight kinetic chains that must be excreted from the body [22], [27]. Second, the molecules used to generate the active radical centers and initiate polymerization can be cytotoxic, and in certain applications, such as cell, protein, and DNA encapsulation, residual initiator molecules are problematic [28], [29]. Additionally, control over the network degradation profile and release behavior is limited due to the network evolution mechanism during chain-growth polymerizations. Finally, for photoinitiated polymers light attenuation by the initiator restricts the maximum attainable cure depth to a few millimeters.

As an alternative to in situ forming networks synthesized via chain-growth polymerizations, Hubbell and coworkers developed degradable networks formed through Michael-addition-type reactions between thiol and acrylate, acrylamide, or vinyl sulfone groups [30], [31], [32], [33], [34], [35], [36]. These networks form through a step-growth polymerization of the thiol and vinyl groups (Fig. 1b). The step-growth nature of these Michael-addition reactions stems from a two-part propagation process where a thiolate ion reacts with a vinyl group to form a carbon-based anion, which then reacts with another thiol group to regenerate another thiolate ion. The repetition of these events in a system of multifunctional monomers generates a covalently crosslinked network with better control of the crosslinking density and corresponding material properties than the photoinitiated chain polymerization of acrylates [32]. Additionally, the degradable segments are incorporated throughout the network, eliminating the high-molecular-weight degradation products containing the backbone kinetic chains formed during chain-growth polymerization. The Michael-addition reaction is catalyzed in a slightly basic environment, eliminating the need to add any initiators. Unfortunately, it is not possible to spatially and temporally control network formation in these materials, and the network gelation rates are considerably slower than those exhibited by the photoinitiated chain polymerization of multifunctional macromers (Fig. 2).

This publication describes a class of degradable thiol-acrylate biomaterials formed through a mixed-mode polymerization mechanism that is a combination of chain-growth and step-growth reactions (Fig. 1c), where both reactions are radically mediated. Three reactions are involved in the propagation mechanism of thiol-acrylate polymerizations and are shown below (Steps 1–3) [37]. Steps 1 and 2 are identical to the classical photoinitiated step growth thiol-ene polymerization in which propagation and chain transfer occur sequentially [38], [39], [40]. An additional propagation step occurs in thiol-acrylate polymerizations due to the ability of the acrylate groups to react with carbon-based radicals (Step 3). This additional reaction results in acrylate homopolymerization, similar to the chain-growth polymerization mechanism of pure acrylates. The unique thiol-acrylate molecular structure evolves from the mixed-mode polymerization mechanism and is directly impacted by thiol:acrylate ratios, transitioning from being more chain-like to more step-like as the ratio of thiol to acrylate groups increases.

Step 1:

Step 2:

Step 3:

In addition to their unusual mixed-mode polymerization mechanism, thiol-acrylates have a number of unique and attractive attributes. They polymerize upon exposure to UV light, with or without added photoinitiator molecules, allowing samples with thicknesses well in excess of 10 cm to be formed. The use of light to initiate the reaction affords spatial and temporal control of the polymerization. The final mass loss profile and degradation induced swelling behavior are controlled through simple changes to the network structure caused by variations in thiol:acrylate ratios. Additionally, changing the thiol mole fraction in the network provides control of the final degradation product's molecular weight distribution. Results herein will demonstrate the advantages of degradable thiol-acrylate networks and compare their behavior to degradable networks formed by the chain polymerization of pure acrylate monomer systems.

Section snippets

Reagents

Pentaerythritol tetrakis(3-mercaptopropionate) (tetrathiol, Fig. 2 1), trimethylopropane tris(3-mercaptopropionate) (trithiol, Fig. 2 2), and poly(ethylene glycol) M¯n 2000 (PEG2000) were purchased from Aldrich. dl-lactide was purchased from Polysciences, acryloyl chloride from Fluka, stannous 2-ethylhexanoate from Sigma, and monobasic potassium phosphate from Mallinckrodt. Triethylamine, dibasic potassium phosphate, methylene chloride, diethyl ether, and benzene were purchased from Fisher

Thiol-acrylate polymerization behavior

Thiol-acrylate photopolymerizations occur very rapidly, even when initiated with relatively low initiator concentrations and light intensities, enabling the formation of networks under physiologically relevant conditions and time scales. The conversion profile of the acrylate homopolymerization (Fig. 3d) displays classical features of multifunctional-monomer chain polymerizations: rapidly reacting upon exposure to UV light, exhibiting autoacceleration and autodeceleration as polymerization

Conclusions

Photopolymerized, degradable thiol-acrylate networks represent a novel class of biomaterials with distinct advantages over the PEG-PLA-(meth)acrylate and Michael-addition networks previously investigated. They rapidly polymerize when exposed to UV light, and enable spatial and temporal control of the polymerization through masking or shuttering of the initiating light source. On a much slower time scale, thiol-acrylates photopolymerize in the absence of any added initiator molecules, allowing

Acknowledgments

The authors thank their funding sources for this work, a grant from the NIH (R01 DE12998), a Department of Education GAANN fellowship and a University of Colorado Beverly Sears Graduate Student Grant to AER. Thiol-acrylate network discussions with Sirish Reddy, as well as statistical analysis discussions with David Clough, were also very much appreciated.

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