Editing Silk (section)

===Biomaterial===
Silk began to serve as a [[biomedicine|biomedical]] material for sutures in surgeries as early as the second century CE.<ref>{{cite journal |last1=Muffly |first1=Tyler |last2=Tizzano |first2=Anthony |last3=Walters |first3=Mark |title=The history and evolution of sutures in pelvic surgery. |journal=Journal of the Royal Society of Medicine |date=March 2011 |volume=104 |issue=3 |pages=107–12 |doi=10.1258/jrsm.2010.100243 |pmid=21357979 |pmc=3046193 |language=en |quote=Galen also recommended using silk suture when available.}}</ref> In the past 30 years, it has been widely studied and used as a [[biomaterial]] due to its [[strength of materials|mechanical strength]], [[biocompatibility]], tunable degradation rate, ease to load cellular growth factors (for example, BMP-2), and its ability to be processed into several other formats such as films, gels, particles, and scaffolds.<ref name="Rockwood-2011">{{cite journal |last1=Rockwood|first1=Danielle N|last2=Preda|first2=Rucsanda C|last3=Yücel|first3=Tuna|last4=Wang|first4=Xiaoqin|last5=Lovett|first5=Michael L|last6=Kaplan|first6=David L|title=Materials fabrication from ''Bombyx mori'' silk fibroin|journal=Nature Protocols|volume=6|issue=10|pages=1612–1631|doi=10.1038/nprot.2011.379|pmc=3808976|pmid=21959241|year=2011}}</ref> Silks from ''Bombyx mori'', a kind of cultivated silkworm, are the most widely investigated silks.<ref>{{cite journal |last1=Altman|first1=Gregory H|last2=Diaz|first2=Frank|last3=Jakuba|first3=Caroline|last4=Calabro|first4=Tara|last5=Horan|first5=Rebecca L|last6=Chen|first6=Jingsong|last7=Lu|first7=Helen|last8=Richmond|first8=John|last9=Kaplan|first9=David L|date=1 February 2003|title=Silk-based biomaterials|journal=Biomaterials|volume=24|issue=3|pages=401–416|doi=10.1016/S0142-9612(02)00353-8|pmid=12423595|citeseerx=10.1.1.625.3644}}</ref>

Silks derived from ''Bombyx mori'' are generally made of two parts: the [[silk fibroin]] fiber which contains a light chain of 25&nbsp;kDa and a heavy chain of 350&nbsp;kDa (or 390&nbsp;kDa<ref>{{cite journal|author2-link=David L. Kaplan (engineer)|last1=Vepari|first1=Charu|last2=Kaplan|first2=David L.|date=2007-08-01|title=Silk as a biomaterial|journal=Progress in Polymer Science|series=Polymers in Biomedical Applications|volume=32|issue=8–9|pages=991–1007|doi=10.1016/j.progpolymsci.2007.05.013|pmc=2699289|pmid=19543442}}</ref>) linked by a single disulfide bond<ref>{{cite journal |last1=Zhou|first1=Cong-Zhao|last2=Confalonieri|first2=Fabrice|last3=Medina|first3=Nadine|last4=Zivanovic|first4=Yvan|last5=Esnault|first5=Catherine|last6=Yang|first6=Tie|last7=Jacquet|first7=Michel|last8=Janin|first8=Joel|last9=Duguet|first9=Michel|date=2000-06-15|title=Fine organization of ''Bombyx mori'' fibroin heavy chain gene|journal=Nucleic Acids Research|volume=28|issue=12|pages=2413–2419|pmc=102737|pmid=10871375|doi=10.1093/nar/28.12.2413}}</ref> and a glue-like protein, [[sericin]], comprising 25 to 30 percentage by weight. Silk fibroin contains hydrophobic [[beta sheet]] blocks, interrupted by small hydrophilic groups. The beta-sheets contribute much to the high mechanical strength of silk fibers, which achieves 740&nbsp;MPa, tens of times that of [[polylactic acid|poly(lactic acid)]] and hundreds of times that of [[collagen]]. This impressive mechanical strength has made silk fibroin very competitive for applications in biomaterials. Indeed, silk fibers have found their way into tendon tissue engineering,<ref>{{cite journal |last1=Kardestuncer|first1=T|last2=McCarthy|first2=M B|last3=Karageorgiou|first3=V|last4=Kaplan|first4=D|last5=Gronowicz|first5=G|title=RGD-tethered Silk Substrate Stimulates the Differentiation of Human Tendon Cells|journal=Clinical Orthopaedics and Related Research|volume=448|pages=234–239|doi=10.1097/01.blo.0000205879.50834.fe|pmid=16826121|year=2006|s2cid=23123}}</ref> where mechanical properties matter greatly. In addition, mechanical properties of silks from various kinds of silkworms vary widely, which provides more choices for their use in tissue engineering.

Most products fabricated from regenerated silk are weak and brittle, with only ≈1–2% of the mechanical strength of native silk fibers due to the absence of appropriate secondary and hierarchical structure,
{| class="wikitable"
!Source Organisms<ref>{{cite journal |last1=Kundu|first1=Banani|last2=Rajkhowa|first2=Rangam|last3=Kundu|first3=Subhas C.|last4=Wang|first4=Xungai|date=2013-04-01|title=Silk fibroin biomaterials for tissue regenerations|journal=Advanced Drug Delivery Reviews|series=Bionics – Biologically inspired smart materials|volume=65|issue=4|pages=457–470|doi=10.1016/j.addr.2012.09.043|pmid=23137786}}</ref>
!Tensile strength
(g/den)
!Tensile modulus
(g/den)
!Breaking
strain (%)
|-
|''Bombyx mori''
|4.3–5.2
|84–121
|10.0–23.4
|-
|''Antheraea mylitta''
|2.5–4.5
|66–70
|26–39
|-
|''Philosamia cynthia ricini''
|1.9–3.5
|29–31
|28.0–24.0
|-
|''Coscinocera hercules''
|5 ± 1
|87 ± 17
|12 ± 5
|-
|''Hyalophora euryalus''
|2.7 ± 0.9
|59 ± 18
|11 ± 6
|-
|''Rothschildia hesperis''
|3.3 ± 0.8
|71 ± 16
|10 ± 4
|-
|''Eupackardia calleta''
|2.8 ± 0.7
|58 ± 18
|12 ± 6
|-
|''Rothschildia lebeau''
|3.1 ± 0.8
|54 ± 14
|16 ± 7
|-
|''Antheraea oculea''
|3.1 ± 0.8
|57 ± 15
|15 ± 7
|-
|''Hyalophora gloveri''
|2.8 ± 0.4
|48 ± 13
|19 ± 7
|-
|''Copaxa multifenestrata''
|0.9 ± 0.2
|39 ± 6
|4 ± 3
|}

====Biocompatibility====
Biocompatibility, i.e., to what level the silk will cause an immune response, is a critical issue for biomaterials. The issue arose during its increasing clinical use. Wax or silicone is usually used as a coating to avoid fraying and potential immune responses<ref name="Rockwood-2011" /> when silk fibers serve as suture materials. Although the lack of detailed characterization of silk fibers, such as the extent of the removal of sericin, the surface chemical properties of coating material, and the process used, make it difficult to determine the real immune response of silk fibers in literature, it is generally believed that sericin is the major cause of immune response. Thus, the removal of sericin is an essential step to assure biocompatibility in biomaterial applications of silk. However, further research fails to prove clearly the contribution of sericin to inflammatory responses based on isolated sericin and sericin based biomaterials.<ref>{{cite journal |last1=Zhang|first1=Yaopeng|last2=Yang|first2=Hongxia|last3=Shao|first3=Huili|last4=Hu|first4=Xuechao|date=2010-05-05|title=Antheraea pernyiSilk Fiber: A Potential Resource for Artificially Biospinning Spider Dragline Silk|journal=Journal of Biomedicine and Biotechnology|language=en|volume=2010|pages=683962|doi=10.1155/2010/683962|pmc=2864894|pmid=20454537|doi-access=free}}</ref> In addition, silk fibroin exhibits an inflammatory response similar to that of tissue culture plastic in vitro<ref>{{cite journal |last1=Wray|first1=Lindsay S.|last2=Hu|first2=Xiao|last3=Gallego|first3=Jabier|last4=Georgakoudi|first4=Irene|last5=Omenetto|first5=Fiorenzo G.|last6=Schmidt|first6=Daniel|last7=Kaplan|first7=David L.|date=2011-10-01|title=Effect of processing on silk-based biomaterials: Reproducibility and biocompatibility|journal=Journal of Biomedical Materials Research Part B: Applied Biomaterials|language=en|volume=99B|issue=1|pages=89–101|doi=10.1002/jbm.b.31875|pmc=3418605|pmid=21695778}}</ref><ref name="Meinel-2005">{{cite journal |last1=Meinel|first1=Lorenz|last2=Hofmann|first2=Sandra|last3=Karageorgiou|first3=Vassilis|last4=Kirker-Head|first4=Carl|last5=McCool|first5=John|last6=Gronowicz|first6=Gloria|last7=Zichner|first7=Ludwig|last8=Langer|first8=Robert|last9=Vunjak-Novakovic|first9=Gordana|date=2005-01-01|title=The inflammatory responses to silk films in vitro and in vivo|journal=Biomaterials|volume=26|issue=2|pages=147–155|doi=10.1016/j.biomaterials.2004.02.047|pmid=15207461}}</ref> when assessed with human mesenchymal [[stem cell]]s (hMSCs) or lower than collagen and PLA when implant rat MSCs with silk fibroin films in vivo.<ref name="Meinel-2005" /> Thus, appropriate degumming and sterilization will assure the biocompatibility of silk fibroin, which is further validated by in vivo experiments on rats and pigs.<ref>{{cite journal |last1=Fan|first1=Hongbin|last2=Liu|first2=Haifeng|last3=Toh|first3=Siew L.|last4=Goh|first4=James C.H.|title=Anterior cruciate ligament regeneration using mesenchymal stem cells and silk scaffold in large animal model|journal=Biomaterials|volume=30|issue=28|pages=4967–4977|doi=10.1016/j.biomaterials.2009.05.048|pmid=19539988|year=2009}}</ref> There are still concerns about the long-term safety of silk-based biomaterials in the human body in contrast to these promising results. Even though silk sutures serve well, they exist and interact within a limited period depending on the recovery of wounds (several weeks), much shorter than that in tissue engineering. Another concern arises from biodegradation because the biocompatibility of silk fibroin does not necessarily assure the biocompatibility of the decomposed products. In fact, different levels of immune responses<ref>{{cite journal |last1=Minoura|first1=N.|last2=Aiba|first2=S.|last3=Higuchi|first3=M.|last4=Gotoh|first4=Y.|last5=Tsukada|first5=M.|last6=Imai|first6=Y.|date=1995-03-17|title=Attachment and growth of fibroblast cells on silk fibroin|journal=Biochemical and Biophysical Research Communications|volume=208|issue=2|pages=511–516|pmid=7695601|doi=10.1006/bbrc.1995.1368}}</ref><ref>{{cite journal |last1=Gellynck|first1=Kris|last2=Verdonk|first2=Peter C. M.|last3=Van Nimmen|first3=Els|last4=Almqvist|first4=Karl F.|last5=Gheysens|first5=Tom|last6=Schoukens|first6=Gustaaf|last7=Van Langenhove|first7=Lieva|last8=Kiekens|first8=Paul|last9=Mertens|first9=Johan|date=2008-11-01|title=Silkworm and spider silk scaffolds for chondrocyte support|journal=Journal of Materials Science: Materials in Medicine|volume=19|issue=11|pages=3399–3409|doi=10.1007/s10856-008-3474-6|pmid=18545943|s2cid=27191387}}</ref> and diseases<ref>{{cite journal |last1=Lundmark|first1=Katarzyna|last2=Westermark|first2=Gunilla T.|last3=Olsén|first3=Arne|last4=Westermark|first4=Per|date=2005-04-26|title=Protein fibrils in nature can enhance amyloid protein A amyloidosis in mice: Cross-seeding as a disease mechanism|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=102|issue=17|pages=6098–6102|doi=10.1073/pnas.0501814102|pmc=1087940|pmid=15829582|bibcode=2005PNAS..102.6098L|doi-access=free}}</ref> have been triggered by the degraded products of silk fibroin.

====Biodegradability====
[[Biodegradability]] (also known as [[biodegradation]])—the ability to be disintegrated by biological approaches, including bacteria, fungi, and cells—is another significant property of biomaterials. Biodegradable materials can minimize the pain of patients from surgeries, especially in tissue engineering, since there is no need for surgery in order to remove the implanted scaffold. Wang et al.<ref>{{cite journal |last1=Wang|first1=Yongzhong|last2=Rudym|first2=Darya D.|last3=Walsh|first3=Ashley|last4=Abrahamsen|first4=Lauren|last5=Kim|first5=Hyeon-Joo|last6=Kim|first6=Hyun S.|last7=Kirker-Head|first7=Carl|last8=Kaplan|first8=David L.|title=In vivo degradation of three-dimensional silk fibroin scaffolds|journal=Biomaterials|volume=29|issue=24–25|pages=3415–3428|doi=10.1016/j.biomaterials.2008.05.002|pmc=3206261|pmid=18502501|year=2008}}</ref> showed the in vivo degradation of silk via aqueous 3D scaffolds implanted into Lewis rats. [[Enzyme]]s are the means used to achieve degradation of silk in vitro. Protease XIV from [[Streptomyces griseus]] and [[Chymotrypsin|α-chymotrypsin]] from bovine [[pancreas]]es are two popular enzymes for silk degradation. In addition, [[gamma radiation]], as well as [[cell metabolism]], can also regulate the degradation of silk.

Compared with synthetic biomaterials such as [[polyglycolide]]s and [[polylactide]]s, silk is advantageous in some aspects of biodegradation. The acidic degraded products of polyglycolides and polylactides will decrease the pH of the ambient environment and thus adversely influence the metabolism of cells, which is not an issue for silk. In addition, silk materials can retain strength over a desired period from weeks to months on an as-needed basis, by mediating the content of [[beta sheet]]s.

==== Genetic modification ====
[[Genetic modification]] of domesticated silkworms has been used to alter the composition of the silk.<ref>{{cite journal
| last1 = Kojima | first1 = K.
| last2 = Kuwana | first2 = Y.
| last3 = Sezutsu | first3 = H.
| last4 = Kobayashi | first4 = I.
| last5 = Uchino | first5 = K.
| last6 = Tamura | first6 = T.
| last7 = Tamada | first7 = Y.
| title = A new method for the modification of fibroin heavy chain protein in the transgenic silkworm
| journal = Bioscience, Biotechnology, and Biochemistry
| volume = 71
| issue = 12
| pages = 2943–2951
| year = 2007
| pmid = 18071257 | doi=10.1271/bbb.70353
| s2cid = 44520735
}}</ref>  As well as possibly facilitating the production of more useful types of silk, this may allow other industrially or therapeutically useful proteins to be made by silkworms.<ref>{{cite journal |last=Tomita|first=Masahiro|date=April 2011|title=Transgenic silkworms that weave recombinant proteins into silk cocoons|journal=Biotechnology Letters|volume=33|issue=4|pages=645–654|doi=10.1007/s10529-010-0498-z|issn=1573-6776|pmid=21184136|s2cid=25310446}}</ref>