Acknowledgements
6.2 Recent Advances of Smart Biomaterials
6.2.5 Smart Biomaterials that Direct Cell Phenotype
in addition to zwitterionic biomaterials, arturo tried to chemically mod- ify alginate, which is one of the most commonly used gel-forming materi- als using a combinatorial synthetic method.78 a large library of the alginate variants has been created, and it has been identified that three triazole- containing analogs (Z2-Y12, Z1-Y15, Z1-Y19 in Figure 6.9) create unique hydrogel surfaces that substantially reduce foreign body reactions as tested in rodents and non-human primates.78 this research group also prepared an alginate gel with a Z1-Y15 modification to encapsulate SC-β cells (a type of insulin-producing human embryonic stem cell) and demonstrated the implant's capability of mitigating the foreign body response and maintaining long-term glycemic control in mice.79
the geometry of materials and devices is an additional factor that mod- ulates the foreign body response;80,81 in particular, the size and shape affect the foreign body reaction and macrophage behavior. omid showed that spherical alginate gel beads of 1.5 mm in diameter had improved biocom- patibility compared with beads of a smaller size or gels of a different shape.82 SLg20 alginate beads of 0.5 and 1.5 mm in diameter were used to encap- sulate 500 ies (islet equivalents) of rat islets and were later transplanted to the intraperitoneal space of streptozotocin (StZ)-induced C57BL/6 diabetic mice, a commonly used type 1 diabetes model (Figure 6.10). transplanted islets encapsulated by 1.5 mm SLg20 alginate could lower the blood glucose to a healthy level for up to 180 days, which is five times longer than islets encapsulated by 0.5 mm SLg20 alginate. it was concluded that the capability for implanted materials to overcome foreign body reactions could be simply manipulated by their spherical dimensions.
Chapter 6156 Figure 6.9 Chemical structures of the three materials.78 reproduced with permission from Macmillan publishers Ltd: a. J. Vegas, o.
Veiseh, J. C. doloff, M. Ma, h. h. tam, K. Bratlie, J. Li, a. r. Bader, e. Langan, K. olejnik, p. Fenton, J. W. Kang, J. hollis- ter-Locke, M. a. Bochenek, a. Chiu, S. Siebert, K. tang, S. Jhunjhunwala, S. aresta-dasilva, n. dholakia, r. thakrar, t. Vietti, M. Chen, J. Cohen, K. Siniakowicz, M. qi, J. Mcgarrigle, S. Lyle, d. M. harlan, d. L. greiner, J. oberholzer, g. C. Weir, r. Langer and d. g. anderson, Nature Biotechnology, 2016, 34, 345. Copyright 2016: nature publishing group.
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00144
157Smart Biomaterials for Cell Encapsulation Figure 6.10 (a) Live/dead staining for islet cells encapsulated in 0.5 mm capsules and 1.5 mm capsules to verify their viability. (b) Blood–
glucose concentration in implanted mice; the one with 1.5 mm capsules shows much longer normoglycemia than the one with 0.5 mm capsules.82 reproduced with permission from Macmillan publishers Ltd: o. Veiseh, J. C. doloff, M. Ma, a. J.
Vegas, h. h. tam, a. r. Bader, J. Li, e. Langan, J. Wyckoff, W. S. Loo, S. Jhunjhunwala, a. Chiu, S. Siebert, K. tang, J. hollister- Lock, S. aresta-dasilva, M. Bochenek, J. Mendoza-elias, Y. Wang, M. qi, d. M. Lavin, M. Chen, n. dholakia, r. thakrar, i.
Lacik, g. C. Weir, J. oberholzer, d. L. greiner, r. Langer and d. g. anderson, Nature Materials, 2015, 14, 643. Copyright 2015:
nature publishing group.
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00144
For example, alginate poly-l-lysine (pLL) was used to encapsulate a murine embryonic stem cell and this encapsulation system was able to control stem cell differentiation into hepatocytes.86 in this system, alginate pLL micro- encapsulation was used as a vehicle to discretely control important culture parameters through variations in alginate composition, pLL concentration, and cell seeding density. delivering signal molecules directly via biomateri- als has many shortcomings, such as their rapid degradation and cleaving.
Significant work has focused on the immobilization (or functionalization) of signal bio-molecules on cell encapsulation materials. tzu-Yun reported a hydrogel assembled from functionalized peptides for neural stem cell encapsulation.87 in their system, rada16, one type of self-assembling peptide (Sap), was used to form a nanofibrous network structure as a cell encapsulating material. as a signal carrier, rada16 was conjugated with a iKVaV sequence at its terminal residue. iKVaV is a motif from the α1 chain of laminin-1, which could promote neuronal differentiation.
in addition to delivering biomedical cues, introducing micro- and nano- scale features onto culture surfaces is another strategy to direct cell differ- entiation.88 Studies revealed that cells could respond to topographical cues, such as elasticity, dimensionality and different combinations of biomateri- als. nathaniel found that manipulating the elasticity of materials could control stem cell behavior in vitro.89 they encapsulated solid-phase porogens into a bulk hydrogel with cells encapsulated. the porogen was degraded via hydrolysis, forming void spaces inside the hydrogel. the chemical composi- tion of the porogen determined its degradation rate, which directed the cell release, potential cell infiltration, and final tissue repair. Kelly examined the phenotypes of native valvular interstitial cells (ViCs) when they were cultured on tissue culture polystyrene (tCpS), and 2d and 3d poly (ethylene glycol) Figure 6.11 Most studied signaling molecules could affect the behaviors of cells in biomaterials applied for tissue engineering.84 reproduced with permission from a. J. Mieszawska and d. L. Kaplan, Mieszawska and Kaplan BMC Biology, 2010, 8, 59. Copyright 2010: BioMed Central.
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00144
(peg) hydrogels (Figure 6.12).90 Cells in 3d hydrogels were smaller and had more rounded morphology, but were less elongated than the ones in tCpS and 2d hydrogels. and most ViCs on tCpS showed organized αSMa stress fibers immunostained in a green color. the results indicated that dimen- sionality affects cell phenotype significantly. Lonnissa showed how different combinations of biomaterials affected the differentiation of a marrow stem cell (MSC) population into different articular cartilage.91 they combined various synthetic and natural biopolymers to create unique niches, such as peg hydrogel with chondroitin sulfate (CS), peg hydrogel with CS and matrix metalloproteinase-sensitive peptide (MMp-pep), and peg hydrogel with hyal- uronic acid (ha). they demonstrated that specific formulations of biomaterials can direct cell differentiation into the articular cartilage of various zones.
Figure 6.12 native valvular interstitial cells (ViCs) were cultured on different media (tCpS, hydrogels in a different dimensionality), staining cells with αSMa (α-smooth muscle actin) (green), f-actin (red) and nuclei (blue) to characterize the myofibroblast phenotype of the ViCs.91 repro- duced from Biomaterials, 74, K. M. Mabry, S. Z. payne and K. S. anseth, Microarray analyses to quantify advantages of 2d and 3d hydrogel cul- ture systems in maintaining the native valvular interstitial cell pheno- type, 31–41, Copyright (2016) with permission from elsevier.
Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00144