Smart Biomaterials that Overcome a Foreign Body Reaction

Acknowledgements

6.2 Recent Advances of Smart Biomaterials

6.2.4 Smart Biomaterials that Overcome a Foreign Body  Reaction

as discussed above, protecting encapsulated cells from immune attack by the host system is one of the biggest barriers in cell encapsulation. encapsu- lating cells in super-biocompatible materials and devices that provide a pro- tective shell barrier is one method for preventing this immune destruction.

however, the immune system recognizes materials or devices implanted in the body as foreign objects, and a foreign body reaction is triggered in most cases.

Figure 6.7    Vascularization of macroporous peg hydrogels embedded with lenti- virus, which could encode for Vegr factor after two and four weeks.⁶⁵ reproduced from Biomaterials, 33(30), J. a. Shepard, F. r. Virani, a. g.

goodman, t. d. gossett, S. Shin and L. d. Shea, hydrogel macroporos- ity and the prolongation of transgene expression and the enhancement of angiogenesis, 7412–7421, Copyright (2012) with permission from elsevier.

Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00144

a foreign body reaction involves the encapsulation of foreign objects within a dense collagen capsule (an avascular network), chronic inflammation, and damage to the surrounding tissue.^70–73 these immune-mediated reactions can lead to degradation, chronic pain, device rejection, and failure. there- fore, encapsulated cells would normally get destroyed after implantation unless the foreign body reaction to the encapsulating materials and devices can be regulated.

the initiation step for the foreign body reaction is believed to involve protein adsorption on the surfaces of implanted biomaterials.⁷¹ it has been hypothesized that non-fouling biomaterials, being able to resist nonspe- cific protein absorption, can attenuate subsequent adverse inflammatory responses.^74,75 Shenfu summarized antifouling materials into two major categories: polyhydrophilic materials and polyzwitterionic materials (table 6.2)⁷⁶. peg and pheMa are two notable non-fouling materials in the Table 6.2    overview of hydrophilic and zwitterionic antifouling materials.⁷⁶

reprinted from polymer, 51(23), S. Chen, L. Li, C. Zhao and J. Zheng, Surface hydration: principles and applications toward low-fouling/non- fouling biomaterials, 5283–5293, Copyright (2010) with permission from elsevier.

Materials protein absorption Cell adhesion

Hydrophilic materials peg-based materials

pS-g-pegMa and pMMa-g-pegMa Yes no

peg-poly(phosphonate) terpolymer Yes no

pLL-g-peg Yes Yes

pegMa Yes no

ppeg_xLys Yes no

poegMa Yes Yes

peo-pu-peo Yes no

peo-ppo-peo Yes no

peo Yes no

peg Yes Yes

py-g-peg Yes no

mpeg-dopa Yes no

mpeg-Mapd Yes no

oeg-SaM Yes Yes

pMoXa Yes no

dendron

glycerol dendron Yes no

hpg Yes no

tetraglyme Yes Yes

dextran Yes no

polysaccharide Yes no

poly (heMa) no Yes

pVa Yes no

polyamines functionalized with acetyl

chloride Yes Yes

Mannitol-SaM Yes Yes

peptide-based SaM Yes no

(continued)

Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00144

polyhydrophilic material category. Compared with these hydrophilic mate- rials, zwitterionic polymers are more promising nonfouling biomaterials because of their biomimetic property, simplicity of synthesis, and availabil- ity of functional groups, and more importantly, the capability to inhibit the foreign body reaction. Lei reported a pCBMa-based zwitterionic hydrogel, which could resist the formation of a foreign body capsule for at least three months at the subcutaneous site as demonstrated in a mouse model.⁷⁷ Zwitterionic pCBMa hydrogel samples after the implantation showed much less capsule formation than pheMa, a typical polyhydrophilic non-fouling material (Figure 6.8).

Table 6.2  (continued)  

Materials protein absorption Cell adhesion

Polybetaine

poly(CBaa) Yes Yes

poly(SBMa) Yes Yes

poly(CBMa) Yes Yes

poly(MpC) Yes Yes

pC-SaM Yes Yes

opC-SaM Yes Yes

Polyampholyte

Sa/tMa-SaM Yes Yes

Ca/tMa-SaM Yes Yes

pM/tMa-SaM Yes no

peptide surfaces derived from natural

amino acids Yes no

poly(tM-Sa) Yes no

poly(MetMa-MeS) Yes no

pdda/pSS Yes no

Figure 6.8    Masson's trichrome staining images to indicate the formation of a col- lagen capsule (red arrow) when encapsulated cells were implanted in mice subcutaneously after four weeks.⁷⁷ reproduced with permission from Macmillan publishers Ltd: L. Zhang, Z. Cao, t. Bai, L. Carr, J. r.

ella-Menye, C. irvin, B. d. ratner and S. Jiang, Nature Biotechnology, 2013, 31, 553. Copyright 2013: nature publishing group.

Published on 03 May 2017 on http://pubs.rsc.org | doi:10.1039/9781788010542-00144

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.