Biomedical Engineering Reference
In-Depth Information
encapsulating CHO cells (Um et al. 2006b). Replacing the traditional bis-acrylamide
crosslinker in a popular bis-gel system (Wang & Pelham 1998), DNA crosslinker of 20-50 nt
long was used for the study of the effect of substrate stiffness on neurite outgrowth (Jiang et
al. 2008b) (
Figure 6C
). In this system, difference in rigidity was created by varying length of
the crosslinker, crosslinking density, or monomer concentration, among which crosslinking
density can be modified via DNA strand delivery in situ. The potential of using these DNA
crosslinked gels in tissue engineering application is promising (Chan & Mooney 2008,
Ghosh & Ingber 2007).
The added advantages by using DNA based macromaterials were further demonstrated
recently in subjecting cells to dynamic stiffness of the substrates (Jiang et al. 2010b, Jiang et
al. 2010c). These studies were motivated by the fact that the micro-environment that cells
reside in within natural tissues is dynamic and undergoes constant synthesis and
degradation in both normal and pathological conditions (Lahann & Langer 2005, Mrksich
2005). Moreover, aging, development, external assault, and pathological processes can also
lead to the alternations in the extracellular matrix (ECM) (Georges et al. 2007, Ingber 2002,
Silver et al. 2003). In addition, at the tissue-implant interface, cells can actively modify
surface of the implants, altering the stiffness of microenvironment of their own or other cells
(Marquez et al. 2006). The changing stiffness could potentially make it possible to achieve
optimal growth of a specific cell property (Jiang et al. 2008b) or direct stem cell
differentiation (Engler et al. 2006) at different time points. These facts make it very desirable
for the biomemetic materials to have the capability of undergoing controlled remodeling
with respect to time. Previously, a limited number of attempts have yielded exciting
findings (Chen et al. 2005, Lahann & Langer 2005, Mrksich 2005), in which dynamic changes
were induced largely through application of environmental factors (e.g., temperature, pH,
and electric field). However, the utility of these approaches in clinical setting could be
problematic. With the unique hydrogen bond based crosslinking, DNA based and
crosslinked materials, therefore, demonstrate time-dependent properties as reflected in
swelling and mechanical modulus, and offer a feasible way of dynamically altering the
macro-scale structure mimicking the
in vivo
conditions (
Figure 8
). Indeed, the initial results
have indicated that encapsulated cells are viable in a DNA-only hydrogel, and in a DNA
crosslinked hydrogel both mechano-sensitive cell types (e.g., fibroblast) (
Figure 9
) and
neuron whose mechano-responses are being appreciated just recently respond to the
changing stiffnesses, and the responses are specific to range and rate of changes and cell
type (Jiang et al. 2010a, Jiang et al. 2010c). A summary of DNA based macromaterials with
dynamic and responsive properties is presented in
Table 2
.
4. Design considerations in DNA based macro-materials
Different than other materials, DNA based macro-materials necessitate some unique
considerations due to involvement of DNA nano-materials.
4.1 Stability
As pointed out in the last section, DNA strand can respond to a variety of environmental
factors such as temperature, pH, and ion concentration and non-environmental factors such
as exogenous DNA or enzyme. While it allows design of smart responsive materials, it also
poses difficulties in maintaining the integrity of structures. Divalent or multi-valent cations
