19_12v2i4_1

19 International Journal of Materials and Biomaterials Applications 2012; 2(4): 19-24

ISSN 2249–9679

Original Article

Natural biomaterial silk and silk proteins: Applications in tissue repair

Amol R. Padol, K. Jayakumar, K. Mohan, Manochaya S. 1

Departments of Pharmacology and Toxicology,

Veterinary College, KVAFSU, Hebbal, Bangalore, India

E-mail: [email protected]

Cell: +91- 9171701585

Received 15 October 2012; accepted 09 November 2012

Abstract

Silk is a natural polymer synthesized and secreted by specialized silk gland of the silk worm. Silk is evolved as an ideal

biomaterial can provide functional insight into relationships between polymer science and molecular biology. Silk proteins

can be recovered from the silk during the processing chain of textile manufacture. The important characteristic of silk,

especially the biocompatibility, non-toxicity and biodegradability, suggest that silks can be used as a biomaterial in

medical and therapeutic applications. As a biomaterial, silk has been used widely as a suture material for years. Impressive

mechanical properties and flexibility of silk allows alteration in its chemical structure. Now a day the use of synthetic

biomaterial for tissue engineering is of great concern due to its safety, toxicity and biocompatibility. Considering the

drawbacks of synthetic biomaterials, the use of silk and silk proteins as natural biomaterial could be of great value.

© 2012 Universal Research Publications. All rights reserved

Key words: Silk proteins, Bombyx mori, biomaterial, wound healing.

1. Introduction

The silk worm Bombyx mori has been domesticated for

centuries and the silk so produced been used in textile

manufacture and as suture material. Basically the silk is

composed of two important proteins namely fibroin and

sericin. The central fibroin core is coated with a covering of

sericin. Silk protein is a kind of protein like collagen,

elastin, keratin, fibroin and sporgin, and is an essential

constituent of cocoon filament [1].

The B. mori is a lepidopteran molecular model and an

important economic insect that is emerging as an ideal

molecular genetic resource for solving a broad range of

biological problems [2]. Sericin protein is useful because of

its special properties viz., antioxidant, antibacterial, UV

resistant, absorbs and release moisture easily and inhibits

the activity of tyrosine kinase [3].

Biomaterial is defined as „any substance (other than a drug)

or combination of substances synthetic or natural in origin,

which can be used any time, as a whole or as a part of a

system which treats, augments, or replaces any tissue,

organ or function of the body‟ [4]. Biomaterials are used in

organ implants, wound healings, drug delivery and other

pharmacological applications. For many reasons natural

biomaterials are the most preferred ones as they are

biodegradable, biocompatible and non-toxic.

The silk fibroin from the Bombyx mori is a structural

polymer possessing unique physical properties including

good biocompatibility and has been established to be

precious material in the field of biomedical engineering

ranging from skin and vascular grafts to substrates for

mammalian cell culture [5]. During decades of use, silk

fibers have proven to be effective in many clinical

applications. Membrane composed of sericin and fibroin is

an effective substrate for the proliferation of adherent

animal cells and can be used as a substitute for collagen.

A silk fibroin based wound dressing have been developed

that could accelerate healing and could be peeled off

without damaging the newly formed skin [6]. Minoura and

coworkers [5] investigated the attachment and growth of

animal cells on films made of sericin and fibroin and they

reported that cell attachment and growth were dependent on

maintaining a minimum of around 90 % sericin in the

composite membrane. Kato et al. [7] provided the first

evidence of antioxidant action of the silk protein by

showing that sericin suppressed in vitro lipid peroxidation.

Biocompatible films can be prepared by blending the

Recombinant Human Like Collagen (RHLC) with fibroin

as a scaffold material for hepatic tissue engineering

applications [8].

Efforts are being made all over the world to discover agents

that can promote wound healing and thereby reduce the

cost of hospitalization and save the patient from amputation

or other severe complications. The need for new

therapeutics for wound healing has encouraged the drive to

examine the nature and value of silk products.

Available online at http://www.urpjournals.com

International Journal of Materials and Biomaterials Applications

Universal Research Publications. All rights reserved

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2. Silk proteins and its composition Silks are generally defined as protein polymers that are

spun into fibers by Lepidoptera larvae such as silkworms,

spiders, scorpions, mites and flies [9]. Silk is one of the

oldest known textile fibers and according to Chinese it was

used as long ago as the 27th

century BC. Silk is recognized

as the “queen of textiles” due to its luster, sensuousness and

glamour [10]. The material has been found in

archaeological sites in China going back 4000 years. The

structure and the content of amino acids in silk proteins are

similar to the skin of human body. Due to its special

chemical structure and chemical composition, it is highly

compatible and absorbed easily with the human skin. Silk is

a natural protein that is made up of 25 - 30 % sericin and 70

- 75 % fibroin proteins [9].

The most important feature of the silk protein is that the

dipeptides and tripeptides can easily permeate into the

blood stream through the dermis layer of skin [1]. Apropos

application scope, the immediate want is realization of

methods to optimize silk utility and value, based on

nutritive worth as human diet and animal feed, precursors

of cosmetic preparations, synthesis of artificial films and

membranes application in pharmaceuticals, biomedical and

biomaterials, vitamins, cardiac and diabetic food

supplements [11].

Silk fibers are 10-20 μm in diameter. Native silk fiber

consists of two types of self-assembled proteins viz., fibroin

and sericin. These two proteins both contain the same 18

amino acids such as glycine, alanine and serine in different

amounts. The central core fibroin is covered by a layer of

sericin, a family of hydrophilic proteins which holds two

fibroin fibers together [9]. There is a kind of proteins that

non-covalently linked these proteins named P25, a 25 kDa

glycoprotein. The fibroin is a giant molecule comprising a

crystalline portion of about two-thirds and an amorphous

region of about one-third. The crystalline portion contains

repetitive amino acids (-Gly-Ala-Gly-Ala-Gly-Ser-) along

its sequence, forming an antiparallel β-sheet and leading to

the stability and mechanical properties of the fiber [12].

Electrophoretic analyses of silk cocoons have revealed

presence of several minor proteins of unknown function.

These low molecular weight proteins are classified as non-

structural silk proteins [13]. The composition of various

amino acids in fibroin is 45.9 % glycine, 30.3 % alanine,

12.1 % serine, 5.3 % tyrosine, 1.8 % valine and 4.7 % other

remaining amino acids.

3. Biological properties of silk

Silk is a high molecular weight natural protein polymer that

has been approved as a biomaterial by the U.S. Food and

Drug Administration (FDA), which has classified it as a

nonabsorbable material according to US Pharmacopeia

[14].

Biocompatibility and biodegradation, apart from the

geometry and mechanical properties are important

considerations for the biomedical applications of silk.

Synthetic polymers like polylactic acid (PLA), polyglycolic

acid (PGA), poly-lactic-co-glycolic acid (PLAGA),

polycaprolactone and natural biopolymers, such as silk,

keratin, elastin, collagen, fibrin clot etc. are extensively

used as biopolymers because of their biological properties.

The natural materials are of considerable interest due to

their structural properties and superior biocompatibility.

However, there are several concerns regarding the

biocompatibility of silk from B. mori. It was considered as

an agent inducing Type I allergic response. Silk was known

to cause complications including asthma and specific up-

regulation of Immunoglobulin E (IgE) levels [9]. It was

observed that sericin was responsible for this sensitization

[15]. When sericin was removed and replaced by wax or

silicone coating in commercial sutures, the allergic

response was not observed. Thus, virgin silk (fibroin

containing sericin gum) is potential allergen but degummed

silk in which sericin is removed is biocompatible. In vitro

evaluation of degummed fibroin demonstrates that the

interactions of fibroin with the humoral components of the

inflammatory system are comparable with those of

polystyrene and poly (2-hydroxyethyl methacrylate), the

two materials used extensively for biomedical applications

[16]. Moreover, silk fibers used as sutures (FDA approved),

are biocompatible and less immunogenic and inflammatory

than collagens or polyesters such as polylactic acid [17].

According to the US Pharmacopeia‟s definition, silk is

classified as non-degradable biomaterial. Although,

according to the literature, it can be considered as a

degradable material over longer times. The reason may be

connected to the fact that silk degradation behavior is

usually mediated by a foreign body response [18].

Depending on the mode of degradation, silk fibroins can be

classified as enzymatically degradable polymers [19].

Enzymes play a significant role in the degradation of silk

fibroins, especially proteolytic enzymes. The degradation

behavior of biomaterials is important in the medical

application in vivo. Within blood, silk is thrombogenic

however, the response is moderate and subsides with time

[9]. The silk protein film is non-irritant; non-sensitizing to

skin and have no effect on serum biochemical profile, [20]

this confirms the safe use silk proteins as a biomaterial.

4. Biodegradation properties of silk As a protein, silk fibroin is susceptible to biological

degradation by proteolytic enzymes such as chymotrypsin,

actinase, and carboxylase [21]. Generally, the

biodegradation behavior of silk has two steps. At first, silk

biomaterials are adsorbed by different enzymes, which

demands that the enzymes must find binding domains on

the material‟s surface. After that, silk biomaterials are

digested by enzymes. The final wastes of silk fibroins are

the corresponding amino acids, which are easily absorbed

in vivo. This is one of advantages of silk biomaterials used

in biomedical field. In in vitro studies of silk degradation

behavior with proteolytic enzymes they cleave the less

crystalline regions of the protein to peptides which are then

capable of being phagocytosed for further metabolism by

the cell [18].

When protease (Protease XIV) was compared with α-

chymotrypsin, silk matrices incubated in the former

enzyme significantly decreased in mass a week later, while,

when in α-chymotrypsin, the mass of the silk matrices

remained unchanged [22]. The enzyme α-chymotrypsin

could degrade the dissolved fibroin proteins but not the


fibroin sheet. In contrast, other enzymes (particularly

protease XIV) extensively degraded the fibroin sheets

demonstrating the potential of protease degradation of silk

fibroin [21].

Biodegradation behavior has great effect on the final

molecular weight after degradation. Upon incubation with

proteolytic enzymes, silk films exhibit a noticeable

decrease of sample weight and degree of polymerization to

an extent which depended on the type of enzymes, on the

enzyme to substrate ratio and on the degradation time [18].

Focusing on three types of enzymes as examples, protease

is more aggressive than α-chymotrypsin or collagenase.

The average molecular weight of silk biomaterials after

degradation with these enzymes follows the order, protease

XIV < collagenase IA < α-chymotrypsin [21].

Silk can be proteolytically degraded and resorbed in vivo

over a longer time period, typically within a year [23]. In in

vivo studies, silks lose the majority of their tensile strength

within one year and fail to be recognized at the site within

two years or even longer [24].

In order to know the biodegradation behavior of silk,

several studies were conducted on implanted silk materials

under the skin of rats in vivo. After 6 weeks post-

implantation, 55 % of silk tensile strength and 16 % of

elastic modulus were found to be lost in the rat model [25].

In another rat model, silk fibers lost 29 % of tensile

strength at 10 days, 73 % at 30 days and 83 % after 70 days

[26].

5. Properties of silk proteins related to wound healing

Silk proteins have promising advantages over synthetic

polymers due to their favorable properties including good

biocompatibility, biodegradability and bioresorbability.

Their physical and chemical properties can be easily

modified to achieve desirable mechanical and degradation

characteristics. Silk fibroin provides an important set of

material options as a biomaterial in biomedical applications

because of its high tensile strength, controllable

biodegradability, haemostatic properties, non-cytotoxicity,

low antigenicity and non-inflammatory characteristics [27].

The silk sericin and fibroin are prospective wound healing

agents and are anti-oxidant and considered as bio-adhesive

mediators of human body [11].

Studies with well defined silk fibers and films suggest that

the core silk fibroin fibers exhibit comparable

biocompatibility in vitro and in vivo with other commonly

used biomaterials such as polylactic acid and collagen [21].

The fibroin powder is known for wound dressing by

regulating exudates of wound providing moist environment

[28]. Silk protein films when bio-modified and

incorporated with Centella asiatica extract, 95 % formic

acid and polyvinyl alcohol would be used as dressing for

the skin injury [29].

Sericin consists of about 30 % serine which is the main

amino acid of natural moisturizing factor in human skin

[30]. Silk protein as a component of spongy sheets can also

accelerate wound healing in rats by facilitating collagen

synthesis [31]. Sericin has more hydrophilic properties due

to presence of several hydroxyl groups and so it is a better

candidate for wound healing [32], [33]. Materials modified

with sericin and sericin composites are useful as degradable

biomaterials, biomedical materials, functional membranes,

fibers and fabrics [34].

Sericin, a major component of silk fiber is selectively

removed from fibroin during the silk manufacturing

process to make silk lustrous and the removed sericin goes

as a waste material [3]. Sericin protein is useful as a

biomaterial because of its unique properties viz., resists

oxidation, antibacterial, UV resistant, absorbs and release

moisture easily, inhibitory activity of tyrosine kinase etc.

Fibroin membrane can be used as a wound dressing

material which causes no toxicity or irritation [35. Silk

fibroin porous material can accelerate wound healing,

improve adhesion and spreading of normal human

keratinocytes and fibroblasts, upgrade the growth and

development of skin tissue [36].

In the clinical treatment of skin defect, silk fibroin is

known to be useful material that promotes collagen

synthesis and re-epithelialization. Furthermore, silk fibroin

was considered to be proper for the generation of

biomedical products such as blended materials because of

its minimal adverse effects on the immune system [37].

Rajendrana and coworkers [38] evaluated the antimicrobial

activity of silk protein sericin by both qualitative (agar

diffusion and parallel streak method) and quantitative

(percentage reduction test) methods against Escherichia

coli and Staphylococcus aureus and concluded that sericin

has antimicrobial properties and might be a valuable

ingredient for the development of antimicrobial textiles.

6. Skin tissue healing potential of silk proteins

6.1. Dermal wounds During decades of use, silk fibers have proven to be

effective in many clinical applications. Tsubouchi [39]

developed a silk fibroin based wound dressing material

which accelerates healing and can be peeled off without

damaging the newly formed skin. The non-crystalline

fibroin film of the wound dressing has a water content of 3-

16 % and a thickness of 10-100 μm. The properties and

application of wound protective membrane made of silk

fibroin was also studied by Wu et al. [40] and concluded

that, the fibroin membrane has good wound healing

properties.

Wound dressing can also be made with a mixture of both

fibroin and sericin [41]. A composite membrane composed

of sericin and fibroin is an effective substrate for the

proliferation of adherent animal cells and can be used as a

substitute for collagen. Cell attachment and growth require

a minimum of 90 % sericin in the composite membrane [5].

Silk protein, sericin is having an antioxidant action which

was proven by Kato and coworkers [7] through in vitro

lipid peroxidation studies.

Angiogenesis during wound healing is also influenced by

the type of suture material used. The angiogenic effect of

suture biomaterials in the rat mesenteric window model

was studied by [42]. They observed a significant increase

of angiogenesis in rats sutured with the silk material.

Wound healing effect of silk fibroin/alginate (an algal

polysaccharide)-blended sponge in full thickness skin

defect was evaluated in rats by Roh and colleagues [43] in

male Sprague-Dawley rats. SF (silk fibroin), AA (alginate)

sponges and SF/AA-blended sponges were prepared by


mixing 1 % (w/v) of aqueous SF and 1 % (w/v) of AA

solution. Each solution was blended with weight ratios of

SF to AA to be 10:0, 5:5 and 0:10 and stirred at room

temperature for 30 min. The blend solution was cast on

polystyrene dishes and freeze dried to obtain test materials.

They reported that the half healing time was significantly

decreased in SF/AA sponge treated SF and AA sponge

treated groups as compared with that of control group. The

area of new epithelialization tissue was markedly increased

from day 7 after treatment in SF, AA and SF/AA sponges

treated groups as compared with those in control group. In

addition, the area of collagen deposition of granulation

tissue was significantly increased from 7 days after

treatment in SF, AA and SF/AA groups as compared with

those in control group. However, there was no difference

among SF, AA and SF/AA groups.

Sericin can also be used as 8 % sericin cream which

promotes wound healing with a significant decrease in

wound area as compared to cream base treated wounds.

The wound healing time is lesser in sericin cream (11 days)

compared with the cream base treated wounds (15 days).

Histological examination reveal that wounds treated with

cream base show incomplete epithelization, ulceration and

increased number of inflammatory cells than that of

wounds treated with sericin cream [44].

Sugihara and colleagues [37] studied the effect of

transparent fibroin film (silk film) on full thickness wounds

in mice. Silk film applied wounds were covered with

regenerated epidermis by 21 days after the excision. In

contrast, wounds dressed with a conventional hydrocolloid

dressing showed an incomplete epidermal growth by 21

days after the excision. Thus, silk film treated wounds

showed a faster wound healing than that of hydrocolloid

treated ones. Histological findings revealed greater

collagen regeneration, less inflammation and less

lymphocyte infiltration of the wounds dressed with silk

film than with hydrocolloid dressing. It can be concluded

that silk film offers advantages over other contemporary

dressings and can be used clinically for wound treatment.

Silk protein based film have significant effect on wound

healing in rats after one time application with increased

hydroxyproline and total protein content of wound tissues.

Histopathologically, wounds treated with silk protein film

encompass good epithelization with keratinization, matured

fibroblast and neovascularization [45].

The efficacy of polarized hydroxyapatite (pHA) and silk

fibroin (SF) composite dressing gel on epidermal recovery

from full thickness porcine skin wounds was evaluated by

Okabayashi and coworkers [46]. They found that the SF gel

containing pHA (pHA/SF) has prominent promotive effects

on wound healing, re-epithelization, and matrix formation

than did the other prepared gel composites. The pHA/SF

effectively advanced the maturation of fibroblast cells

benefiting from its structural advantages and stored

charges. The pHA transforms the SF structure into a porous

three dimensional scaffold.

6.2. Application in other tissue injury

A study was conducted by Gobin and colleagues [47], to

investigate the feasibility of using silk fibroin and chitosan

blend (SFCS) scaffolds for ventral hernia repair in guinea

pigs. In this study, SFCS was compared with biodegradable

human acellular dermal matrix (HADM) and

nonbiodegradable polypropylene mesh by implanting each

to repair an incisionally created ventral hernia in the

abdominal wall using an inlay technique. At 4 weeks, both

HADM and SFCS underwent remodeling by host tissue,

but polypropylene mesh resulted in extensive bowel

adhesions and scarring. Abdominal wall repairs with SFCS

showed tissue remodeling in all three dimensions, with

seamless integration at the interface with adjacent native

tissue. The SFCS repair sites remained intact, and their

mechanical strength was similar to that of the native

abdominal wall despite greater degradation and remodeling

of SFCS than of HADM. The deposition of new

extracellular matrix consisting of collagen and ground

substance, uniform vascularization, and cellular infiltration

in SFCS repair sites contributed to the increase in

mechanical strength of the regenerated tissue. Thus,

concluded that SFCS is a potentially useful material for

clinical abdominal wall reconstruction, since it becomes

remodeled and integrated into the surrounding abdominal

wall and maintains adequate tensile strength.

The effect of silk fibroin film for repairing urethral defect

in rabbits was evaluated by Liu and coworkers [48] in

rabbits. Histological observation and immunohisto-

chemistry showed that the implanted silk fibroin film for

defect repair was degraded completely at 16 weeks and the

defect was repaired with smooth urethral mucous

membrane lining and orderly arranged smooth muscle cells

without any signs of urethral stricture when compared to

control group. Also, on immunohistochemistry identified

that the cells lining the defect area was the urethral

epithelial cells.

Silk fibroin can be used as biomaterial coating used in

tracheal defect reconstruction. Silk fibroin when embedded

as an artificial implant material coating to reconstruct

tracheal defects, there was no foreign-body granuloma or

macrophagocyte infiltration around the silk film. The

tracheal reconstruction study showed a normal mucous

membrane with normal cilial growth on the artificial

implant and no visible granulation tissue in the

reconstructed tracheal cavity [49]. 3D scaffolds prepared

from silk fibroin of Indian tropical tasar silkworm

Antheraea mylitta may be employed as suitable biomaterial

for the establishment of therapies for cardiac diseases

which requires mechanical support [50].

7. Conclusion

Many investigations have been done to understand and

describe silk and silk protein properties as a functional

biomaterial. This is rather a new field in biomedical

engineering, but it already gives very promising results.

Silk have amazing tensile properties, a biocompatible

structure and good degradation rates. Also silk proteins are

known to activate the blood clotting cascade by binding to

fibrin and fibrinogen. Various studies elucidate the in vivo

degradation profiles for the silk materials and

understanding the utility of silk based advanced

biomaterials for a wider range of applications.

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Source of support: Nil; Conflict of interest: None declared

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