COLLAGEN

AS A POTENTIAL BIOMATERIAL
IN BIOMEDICAL APPLICATIONS

Assist. Prof. Dr. BETÜL GÜRÜNLÜ

Anahita Haddadian
234314905

17.05.2024
Introduction
Collagen is a type of biological macromolecule that forms a highly organized, three-
dimensional structure and can accommodate various components due to its network-like
architecture. It is widely used as a biomaterial across different fields due to its versatile
properties such as biodegradability, biocompatibility, and easy availability [1-3].

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The molecular weight of acid-soluble collagen is approximately 300 KDa, with an
electrophoretic pattern showing two α chains and a β chain. The α chains are
categorized as α1 and α2, with molecular weights below 200 KDa, while the β chain
is a dimer with a molecular weight above 200 KDa [4,5].

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Commercially available collagen exists in different types and forms found in various
tissues like bone, skin, tendons, ligaments, cartilage, blood vessels, the vitreous
humor in the eye, and intervertebral discs.
The survey of the fundamental properties of collagen forms a basis for understanding
the biomedical role of collagen in fields such as ophthalmology, tissue engineering,
wound healing, and delivery vehicles [6].
By considering the specific characteristics and wide applicability of collagen isolated
from various biological waste materials, we have discussed its role in selected
biomedical applications.

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ISOLATION OF COLLAGEN FROM VARIOUS SOURCES
FOR ITS POTENTIAL BIOMEDICAL APPLICATION
Collagen can be isolated from various wastes products such as bovine limed split
wastes [7], fish skin, bone, and fin [8], the outer skin of cuttlefish [9], skins of Baltic
cod, chicken skin, skins of young and adult Nile perch, skin and bone of big eye
snapper, solid wastes of leather industry, skin of deep-sea redfish, skin of threadfin
bream, short tendons of slaughtered cattle [4], mangrove archaeogastropoda [10],
swim bladder of catfish, natural marine source jellyfish species, etc. The isolated
collagen from various sources seeks its useful application in various fields such as
biomaterials, functional additives, cosmetics, and pharmaceutical industries.
Collagen can also be isolated from chromium-containing leather wastes (CCLW)
which may be useful for biomedical applications.

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Collagen usually exhibits a triple helical strand (Fig. 1a) which is rich in amino acids
such as glycine and proline/hydroxyproline. The fibrous nature of the isolated collagen
can be understood by visualizing the surface morphological structure using scanning
electron microscopic (SEM) images (Fig. 1b).

Fig. 1. (a) Schematic diagram of triple helical structure of collagen and (b) SEM image
of isolated collagen from CCLW.
DIFFERENT TYPES OF COLLAGENS
Collagen-based biomaterials are widely used as scaffolds for bone
formation, tissue substitutes, gene delivery, and as biomarkers in
osteoarthritis. Various types of collagen with their functions are given
below in Table 1.

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Table 1. Different types of collagens and its application.

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 Applications of collagen
Collagen, a versatile biomaterial finds its application in various fields and has its
wide applicability in the medical field. Since it exists in various forms it plays a
vital role in the biomedical field. Various formulations and their respective
applications are detailed as follows:
1) Shields in ophthalmology, 2) Sponges for burns and wounds, 3) Mini-pellets for
protein delivery and drug delivery, 4) Controlling material for transdermal delivery,
5) Nanoparticles for gene delivery, 6) Used in the form of film, sheet, and disc for
collagen-based drug delivery formulations for tissue infections, 7) 3D scaffold for
cell culture-based biological studies such as evaluation of tissue calcification and for
the embedding of single-cell suspension for tumorogenic study, 8) An effective
biomaterial that forms organoids or neo-organs in gene therapy. Apart from this, it
also finds its application in tissue engineering including skin replacement, bone
substitutes, and artificial blood vessels and valves.
The major biomedical field applications are shown as a schematic layout (Scheme
1) and their detailed descriptions are covered in the review as follows.

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Scheme 1. Schematic presentation of collagen for biomedical applications.

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 Tissue engineering application
A variety of substances, including metals (titanium), ceramics (alumina), synthetic
polymers (polyurethanes, silicones, PGA, PLA, PLGA, polyanhydrides), and natural
polymers (chitosan, glycosaminoglycans, collagen), are utilized in biomaterial
production for biomedical applications. Collagen-based biomaterials are particularly
notable in tissue engineering due to their distinct properties [11]. They enhance tissue
repair in various areas, such as bone, tendon, ligament, and skin, owing to their
biocompatibility with native collagen [2]. This biocompatibility enables collagen to
serve as a cell scaffold, contributing to its role in tissue engineering and biomaterial
design [2]. Its use in tissue engineering has seen significant growth in recent decades
[3].
Techniques like air-drying and freeze-drying are employed to create dense and porous
collagen membranes for wound dressing and tissue engineering [12]. Incorporating
collagen and fibrin into hydrogel scaffolds plays a crucial role in promoting cell
differentiation, particularly with adipose-derived stem cells (ASCs) [13]. Overall,
collagen-based biomaterials play a pivotal role in advancing tissue engineering
applications and have considerable potential in biomedical research and clinical
practice [2].

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  Ophthalmic applications
The newer ophthalmic forms such as polymeric gels, colloidal systems, cyclodextrins,
and collagen shields provide an improved ocular drug bioavailability when compared
to the conventional dosage. This increases the drug availability, retentivity,
sustainability, penetrability, and solubility at the site of action. Apart from this, the
advanced formulation differs from conventional dosage in many aspects such as
applicability, acceptability, and utility which can be easily understood. So, the recent
developments in ophthalmic research will pay much attention to developing a non-
invasive sustained drug release and a promising approach with an improved
ophthalmic therapy for the treatment of vision-threatening disorders.
An improved ophthalmic method of treatment remains a good platform for the
treatment of eye disorders due to the improvement in the properties of drug delivery
systems [14].

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  Collagen shields
Collagen shields, derived from porcine or bovine scleral collagen, possess
biodegradability and cross-linking properties, enhancing their dissolution capacity
under the eye for up to 72 hours. They serve as drug delivery vehicles and protective
agents, accelerating epithelialization of the ophthalmic membrane and delivering
medications such as antiviral, antifungal, and immunosuppressive agents. Collagen
shields soaked in antifungal agents like amphotericin prevent keratomycosis post-
cataract surgery [15].
Scleral collagen is also used as a corneal bandage lens in surgical and traumatic
corneal conditions, offering efficient preparation for eye infections when pre-soaked
in pharmacological agents. Pre-soaked collagen shields, tailored for drug delivery,
offer varying dissolution times and sustain higher levels of ocular activity with water-
soluble antibiotics or steroids. Recent studies demonstrate a significant reduction in
corneal ulcers by placing collagen shields bilaterally in pet rabbit corneas.

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  Eye implants
Eye implant is a form of sub-retinal drug delivery system that has been developed to
overcome the limitations of current treatments for retinal diseases [16]. The eye
implant also plays a vital role in treating diseases such as glaucoma and other
gastrointestinal disorders. Apart from this, the implants are synthesized based on the
electronic principle. One such implant synthesized is a microelectromechanical
implant which is used to stimulate the retinal structures so that the loss of vision may
be restored with the stimulatory function of retinal membranes. Similarly, a chronic
microelectronic retinal prosthesis is synthesized and implanted permanently in the eye
of the blind in connection with electronic components and the digital camera in order
to detect the light, movement, and recognition of shapes.

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  Drug delivery matrix
Collagen in the form of gel acts as a drug delivery matrix due to its characteristic
properties such as flowability, injectability, and biocompatibility. These essential
properties help in achieving sustained release action of therapeutic molecules and be
an attractive biomaterial in tissue engineering applications. Usually, the nonfibrillar
collagen possesses a lesser pore size when compared to the fibrillar collagen and this
effective pore size plays a major role in tissue engineering studies since the cells have
to be retained within the gel after its proliferation and differentiation. Collagen gel
with suitable pore size alone can act as an effective biomaterial when compared to the
other commercially available forms of collagen.

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  Immunolocalization effect
The cell adhesion assay, mediated through membrane receptors was carried out using
collagen isolated from jellyfish. The molecular determinant present in the isolated
collagen was involved in human cell adhesion through integrins and heparin sulfate
receptors existing on the surface of the human cells.
This cell adhesion property was recently highlighted using the plating technique. The
in vitro study results suggested that after in vivo implantation, the jellyfish collagen
may promote cell adhesion, proliferation, or migration of the human cells. The
biocompatibility and cell adhesion assay results suggest that the collagen isolated
from the marine source may act as an ideal substitute for bovine or human collagen in
particular biomedical applications.

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  Sponges for burns/wounds
Collagen due to its special properties such as porosity, meshwork, sponge-like
structure forming capacity, good biocompatibility, and surface properties aid in
finding its biomedical application. Such type of collagen is used in the treatment of
skin disorders such as burns and ulcers. Epidermal growth factor (EGF) loaded in
collagen sponge matrix helps in the formation of the dermal matrix and improves the
wound mechanical strength by wound contraction and scar tissue development [17].
Succinylated collagen prepared as a bilayer dressing material when loaded with
chemotherapeutic agents such as ciprofloxacin is used for the controlled release of
drugs to attain sustained release activity [18]. Collagen sponge when loaded with
therapeutic substances such as cytokines and growth factors helps in the proliferation
of keratinocyte and fibroblast donor cells formation.

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The mechanism of wound healing using a collagen sheet can be easily understood
with the diagrammatic representation given below (Fig. 2). The rate of the wound
healing process depends on factors such as oxygenation, age, gender, secretion of sex
hormones, stress, obesity, nutrition, alcoholism, and smoking, medications,
immunocompromised conditions and in certain diseased states. Thus, a collagen
sheet can be used for treating skin disorders.

Fig. 2. Schematic diagram depicting the release of therapeutic substance from a

collagen sheet to aid wound healing.
Conclusion
In conclusion, collagen, a biological macromolecule can be isolated using simple
methods from the biological connective tissue wastes. The isolated collagen from
different sources finds its versatile role in pharmaceutical and biomedical
applications.
Collagen finds its potential applications in fields such as ophthalmic, orthopedics,
burn/wound management, and tissue engineering applications. Apart from this, it
plays a major role in delivering therapeutic substances such as drugs, proteins, and
genes at the targeted site. Thus, this review highlights the benefits of collagen in
various biomedical fields and its isolation from biowastes which helps in reducing
environmental pollution.

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