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In the field of medicine, controlled drug delivery has become a major challenge due to inefficiency of drug at critical parameters such as permeability, solubility, half-life, targeting ability, bio- & hemocompatibility, immunogenicity, off-target toxicity and biodegradability. Since several decades the role of drug delivery module has been a crucial parameter of research and clinical observations to improve the effectiveness of drugs. Biomaterials- natural or artificial are mainly used for medical application such as in therapeutics or in diagnostics. Among all the biomaterials, collagen based-hydrogels/ films/ composite materials have attracted the research and innovations and are the excellent objects for drug delivery, tissue engineering, wound dressings and gene therapeutics etc. due to high encapsulating capacity, mechanically strong swollen structural network and efficient mass transfer properties. Substantial developments have been performed using collagen-based drug delivery systems (DDS) to deliver biomolecules with better efficacy. In spite of significant progress, several issues at clinical trials particularly targeting of intracellular molecules such as genes is still a challenge for researchers. Experimental results, theoretical models, molecular simulations will boost the fabrication/designing of collage-based DDS, which further will enhance the understanding of controlled delivery/mechanism of therapeutics at specific targets for various disease treatments.
Department of Biosciences, Jamia Millia Islamia, Srinivasa Ramanujan Block, New Delhi, India
*Address all correspondence to: averma@jmi.ac.in
1. Introduction
Collagen is unique and major structural protein of extracellular matrix (ECM) and plays crucial role to the structural integrity of tissues/organs and cellular growth in vertebrates and other organisms, constitute around 30% of the total protein content of mammal’s body, involved in mechanical protection of tissues and organs such as skin, tendons, ligaments, bones, cartilage, blood vessels, cornea and nails etc. (Figure 1) [1, 2, 3, 4, 5, 6]. More than 50% in the skin and more than 90% of extracellular proteins in the tendon and bone is made up of collagen [7, 8].
Figure 1.
Collagen’s occurrence in different body tissues.
The unique feature of collagen molecule is triple helix structure made by three identical or non-identical polypeptide chains. Each polypeptide chain comprises around 1000 amino acids and the chains are supercoiled in left handed manner around the axis with staggering of residues between adjacent chains, give rise to triple helix right handed structure [9]. Each chain is having the repeated sequence of (Gly-X-Y)n, whereas X and Y are mostly proline and hydroxyproline residues [1, 10, 11]. At present, 30 different types of collagens have been characterized and reported in literature [12]. Among all the different variants of collagen, type I, II, III, V and XI represent more than 90% of human fibrillar collagen and is majorly distributed in dermis, hair, bone, cartilage, ligament, tendon and placenta [13]. Other types such as type IV and VIII form the network frame of basement membranes [12, 14]. Type I collagen has very important role in medicine as well as in development of medical devices, artificial implants, drug carriers for controlled release and scaffolds for tissue regeneration [5, 15, 16]. Being the highly versatile, structurally unique and biocompatible protein substance, the collagen can be developed into different types of drug/active substance carrier module such as hydrogels, microparticles and films etc. [3, 7].
According to Hench and Erthridge, 1982 [17], “a biomaterial is used to make devices to replace a part or a function of the body in a safe, reliable, economic, and physiologically acceptable manner.” Raghavendra et al. [18] has mentioned the other definitions of biomaterial are “materials of synthetic as well as of natural origin in contact with tissue, blood, and biological fluids, intended for use for prosthetic, diagnostic, therapeutic, and storage applications without adversely affecting the living organism and its components” [19] and “any substance (other than drugs) or combination of substances, synthetic or natural in origin, which can be used for any period of time, as a whole or as a part of a system which treats, augments, or replaces any tissue, organ, or function of the body” [20]. Application of biomaterials in physiological systems is possible due to competent and stable features of biomaterials [21] which can be achieved with proper combination of mechanical, physical, chemical and biological attributes [22]. Modern biomaterials are designed and developed singly or in combinations of polymers, metals, composite materials and ceramics etc. [18].
In the field of medicine, collagen is one of the most studied biomaterial or biopolymer and according to Cheng et al. [23], around 260,000 literature articles (at present, the number is many more than reported) reported it as pivotal component in tissue regeneration and so called as ‘the steel of the biological material”. Collagen is the main biopolymer of ECM of vertebrates and invertebrates and has the capability to interact with large number of biomolecules leading to various biological reactions/changes under normal or pathological processes in the body, inspiring the scientists to develop the various formulations based on collagen [24, 25, 26]. The attributes for the testimony of collagen’s usage in wide scenario of medicine are its cosmopolitanism, high biocompatibility, hemocompatibility, biomimetic and biodegradability and to make composite biopolymer with biomaterials like chitosan (CHS), alginate (ALG), cellulose (CL), hyaluronic acid (HA), glycosaminoglycans (GAGs) as well as synthetic materials like carboxy methyl cellulose (CMC), poly vinyl alcohol (PVA), poly ε-caprolactone (PCL), poly ethyl methacrylate (PEMA) etc. in different formulations [27, 28, 29].
Now it is well established that collagen has good elasticity, physical, mechanical, enzymatic and thermal stability inside the body environment, but after extraction and utilization these properties are compromised at large scale [30, 31, 32], so the additional need of chemicals, chemical and physical processes are required to develop the stable biomaterial. Though extracted collagen is a promising drug delivery material in the field of ophthalmology but can be easily degradable in vitro due to disruption of natural intermolecular crosslinks of lysine and hydroxylysine residues during isolation and purification process [33]. The weaknesses of extracted collagen such as mechanical and thermal strength, enzymatic degradation can be reduced with the help of various methods of chemical, physical and enzymatic crosslinking, covalent conjugating, grafting polymerization or blending. The blended collagen-based biomaterials like hydrogels, films, microspheres and nanoparticles (NPs) have low immunogenicity, good absorption, hemostatic property and synergism with other bioactive compounds or loaded drugs and remain unaltered after several processes. The requirement of mechanical, pH, enzymatic, thermal stability is not provided alone by collagen for a controlled DDS but can be achieved with combination of CHS or ALG for release of analgesics, chemotherapeutic molecules and natural bioactive agent like curcumin or aloe vera. The blended biopolymer will have the combined desired properties of the separate material. Hydrogel of blended collagen-CHS have antibacterial, antifungal, anti-carcinogenic and immunogenic attributes [34, 35, 36, 37]. Blended collagen-CL based hydrogel has properties like biomimetic and hemostatic from collagen while mechanical strength and antibacterial characteristic from CL. In the field of ophthalmology blended collagen-based hydrogels with CHS or ALG are applied for corneal disease treatment exhibiting good mechanical and thermal attributes along with transparency. The films, microspheres, membranes and scaffolds of blended collagen-based materials are used in wound dressing due to moisture retaining, low adhesion, absorption of blood and tissue exudates, anti-infective and permeability properties [32, 38, 39, 40, 41]. The sources and possible applications of most utilized material of blended biopolymers along with important features like stability, toxicity and biomedical are presented in Table 1.
Collagen is the most abundant vertebrate protein and mostly used biopolymer and with variety of physiological features like biocompatible, low immunogenic, self assembling fibril formation etc. The collagen is mechanically strong and durable in vivo but after the isolation and purification processes is vulnerable to degradation in vitro due to dissociation of natural crosslinks and assembly structure by neutral salt, acid alkali or proteases and quality of extracted collagen is inferior to native state (Figure 2) [42, 55]. The researchers are attempting to make the suitable collagen-based biomaterial with properties of increased mechanical strength, reduced enzymatic degradation, stability, solubility and low toxicity by introducing exogenous crosslinking [42, 56]. The introduced intermolecular crosslinking prevents the unknotting of collagen fibrils produced by heat and advancing the thermal stability along with increased tensile strength, stiffness, compressive modulus and decreased extensibility [57, 58, 59, 60]. The exogenous natural or chemical crosslinks could significantly reduce the enzymatic degradation of collagen by blocking the cleavage site [61].
Figure 2.
Native crosslinking in the collagen molecules.
Though collagen-based crosslinked biopolymers are producing significant results in the field of biomedicine and biotechnology, still no standard method is applicable to the formulation of improved non-toxic and biocompatible hydrogels, films and matrices etc. Different crosslinking strategies such as chemical, physical or enzymatic are applied to achieve the collagen-based materials with desired properties for drug delivery and other applications [62].
3.1 Chemical crosslinking
The most used crosslinking method is with chemical agents due to ease of application, less time consuming and cost effective. The most commonly used chemical reagents are formaldehyde (FA) and glutaraldehyde (GTA). FA reacts with the ε-amino group of lysine and hydroxylysine residue of collagen to form imine as an intermediate followed by crosslink with tyrosine or with amide group of asparagine or glutamine residue. FA-crosslinked products generated brittleness, significant toxicity and unfavorable reactions, hence not preferred in biomedicine [7]. Another agent GTA is widely utilized for crosslinking of collagen, based on high reactivity and low cost. The low concentration of FA and GTA produced brittle and low uniformity of composites while high concentration led to major cytotoxic effects. Several methods have been applied to remove the unreacted GTA, due to its cytotoxicity the use of GTA at present scenario is still debatable [28, 42]. Hexa-methylene-diisocyanate (HDC) was used as an alternative to GTA, but in contrast to GTA, HDC showed less severe primary and secondary cytotoxicity during cell proliferation as compared to non-crosslinked material [63]. Charulatha & Rajaram [64] evaluated the biocompatibility of collagen membranes cross-linked with 3,3′-dithio bis-propionimidate (DTBP) and dimethyl suberimidate (DMS). Both DTBP and DMS showed lower toxicity than GTA and as the better substitute for crosslinking. The polyepoxy compounds such as ethylene glycol diglycidyl ether, glycerol polyglycidyl ether and methyl glycidyl ether were used as crosslinker [65]. The epoxy group reacts with amino group of lysine residue for crosslinking similar to GTA. The polyepoxy crosslinked material showed acceptable cytotoxicity [66].
Due to non-toxicity and water solubility, the carbodiimides and acyl azides showed significant crosslinking with collagen. Carbodiimides like 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and N-hydroxy succinimide (NHS) are better candidate than aldehydes, HDC and polyepoxy compounds due to formation of amide bonds between –COOH and –NH2 group of collagen without becoming the part of actual linkage. Van Wachem et al. [67] compared the four crosslinking methods i.e. GTA, HDC, acyl azide and EDC for the assessment of biocompatibility and tissue regeneration ability and EDC crosslinked material showed best results among the four tested methods. Pieper et al. [68] showed that EDC crosslinked collagen expressed no cytotoxicity, slow enzymatic degradation and decreased calcification.
Non-toxic, biodegradable and biocompatible natural compounds as promising cross-linkers like alginic acid (anionic block copolymer) from brown algae, iridoid compounds from the fruits of Gardenia jasminoides and Genipa americana [69], oxidized alginate [70], dialdehyde starch [71], D, L-glyceraldehyde [72], natural polyphenols and dialdehyde- carboxymethyl cellulose [73] have been broadly examined. In recent years usage of polyphenols such as caffeic acid (CA) and tannic acid (TA) [74], proanthocyanidin [75], procyanidin [76], epigallocatechin gallate (EGCG) and epicatechin gallates (ECG) [77] and other tannins [78] have been increased due to antioxidative, anti-inflammatory, antimicrobial, cardioprotective, antithrombotic, pharmacological and therapeutic possibilities. According to Jackson et al. [77] TA, EGCG and ECG showed stabilization of collagen implant for long period at very low concentration and protection against collagenase more effectively than GTA and carbodiimides. In contrast to GTA, natural crosslinkers have disadvantages like long term storage and degree of crosslinking.
3.2 Physcial crosslinking
Physical techniques like ionizing radiation (X-ray and γ-ray), UV light and dehydrothermal treatment and dye-mediated photo-oxidation are used as crosslinkers for collagen based formulations. The physical crosslinking relies on the factors like amount of radiation, temperature, hydration conditions, electron beam intensity and UV denaturation [43]. Photosensitizer riboflavin in combination with UV-irradiation produced the similar results of crosslinking by GTA without cytotoxicity to reduce the harmful effects of physical and chemical crosslinking [45]. UV- light mediated crosslinking generated the denaturation and conformational modifications of collagen molecules which opposed the stabilization of UV-induced crosslinked product [79]. Dehydrothermal treatment resulted into the complex of collagen with anatomically accepted structures without contraction, curling or deformity for longer duration without the involvement of chemical crosslinking [80]. In contrast to chemical crosslinking the heating disrupted the triple helical conformation of collagen and increased the degradation by enzymes [81]. Overall the physical crosslinking methods are simple and safe for the production of splendid biocompatible biomaterials in comparison to exogenous cytotoxic chemical crosslinkers.
3.3 Enzymatic crosslinking
Enzymatic approaches have gained interest due to brilliant specificity and accurate reaction kinetics and to surmount the difficulties with chemical methods. Enzymatic crosslinkers can be categorized into oxidoreductases, transferases and hydrolases based on the catalytic reaction [82]. The oxidative enzymes tyrosinase and laccase [83] along with acyltransferase-transglutaminase have the capacity to modify the protein substrate to enhance the quality of crosslinked biomaterials [84]. Transglutaminases are calcium dependent and catalyze the reactions in broad range of pH and temperatures. Microbial origin biodegradable transglutaminases can catalyze the crosslinking in the concentration dependent manner [85, 86]. Exogenous lysyl oxidase catalyzes the lysine residue into highly reactive aldehydes leading to the formation of crosslinks in the ECM proteins. The pre-treatment of lysyl oxidase promoted the maturation of native and engineered collagen tissues both in vitro and in vivo with reference to increased tensile modulus and pyridinoline crosslinking [87].
Comparing all the crosslinking strategies the chemical method is the most preferred due to generation of consistent and high degree of crosslinking [88]. The physical method is used as a appurtenant crosslinking approach. Enzymatic approach alleviates the shortcomings produced by chemical and physical crosslinking methods, but it is time consuming and expensive [89]. In recent years, the use of natural and eco-friendly biocompatible crosslinkers has increased and become the very promising agents. The natural substance- genipin obtained from irridoid glucoside (geniposide) is one of the important crosslinker with great potential in the field of biomedicine. Genipin is very expensive in contrast to other natural crosslinkers, while TA is cheap and easily accessible compound for crosslinking [89].
Traditional drugs have been the main concern to effectively treat the several diseases. The introduction of classical drug in therapeutics at high concentrations generally develops the substantial and sometimes severe consequences. The development of effective DDS for the efficacious augmentation of particular drug at desired target and at optimal concentrations for necessary duration has been the critical concern of clinical investigations and research since several years. To achieve the targeted or controlled local drug delivery, both synthetic and natural drug delivery materials are playing the important role.
At present, DDS have been developed based on polymers, nanomaterials and lipids etc. for the attachment or encapsulation of drugs to target the delivery or controlled release for long duration [90, 91]. Collagen based biomaterials or composite materials have become the important DDS due to specific pore size for active drug or principal load, effective fibrillar network, enzymatic degradation, long term stability in vivo, biocompatibility, low antigenicity, highly reduced toxicity and safety features [92]. The chemical modifications of –OH, –NH2 and –COOH groups on collagen molecule making it more relevant and promising candidate in the domain of biomedicine. Collagen based biomaterials can be formulated into different forms according to desired medical application of drug delivery as mentioned in Figure 3. Various types of collagen based bioformulations such as hydrogels, films, sponges, scaffolds, matrices, aqueous injections, microspheres, micro-particles, micro-beads, NPs, nano-composites, nanofibres, shields, inserts, tubes, coatings, monolithic devices, implants and dressings etc. are applied for various drug delivery applications, tissue growth and regeneration. In Table 2, the type of formulations, synthetic or natural polymeric support material, active compound or drug and specific biomedical application has been summarized.
Figure 3.
Different types of collagen based biomaterials used for drug delivery.
Application of collagen and collagen based material in drug delivery systems (DDS).
4.1 Gel/hydrogel
Hydrogels are three dimensional (3-D) crosslinked arrangements of similar or different types of polymeric molecules with the property of absorbing and retaining the optimum quantity of water or biological fluid without degrading or losing the network structure. The material can be categorized as hydrogel, if the water content in the material is at least 10% of the total weight or volume of hydrogel [38]. The water molecules in the hydrogel provide the freedom of flexibility to design the natural tissue like environment. Hydrogels can be synthetic or natural with different chemical constituents and having different mechanical, physical and chemical attributes according to biomedical application. Hydrogels can be hydrophilic or hydrophobic in nature. Hydrophilic hydrogels possess hydroxyl (–OH), amine (–NH2), carboxyl (–COOH), amide (–CONH–CONH2) and sulphonic (–SO3H) group for the swelling and absorbing property. The hydrophobic polymers show low swelling feature despite having improved mechanical, physical or chemical strength.
Drug transport within hydrogel can be regulated by altering the network/mesh size or the interactions with drugs using chemical methods [172, 222]. If the loaded drug is smaller than the crosslinked network of hydrogel, it can simply diffuse through the hydrogel while the larger drug molecules are entrapped within the hydrogel network and can be released after the degradation of the mesh. The biopolymer and its crosslinked network can be degenerated via slow hydrolysis of peptide or ester linkage or cleaving the thiol-related bonds, or through the enzymatic activity [223]. By the incorporation of non-covalent or covalent drug-matrix interactions, drug release from the hydrogel can be tuned [224, 225]. The characters mainly mesh size, crosslinking chemistry and drug interactions facilitate the better handling of drug transport through hydrogel. ECM-based hydrogels are the preferred choice for local drug delivery due to mechanical and biochemical support through cell-matrix interactions and diffusion and infiltration of small drug molecules in between crosslinked polymeric network [172].
Collagen alone is used for the delivery of several drugs and active principles such as keterolac, nerve growth factor (NGF)-β, TA, curcumin and royal jelly etc. for various biomedical purposes like anti-inflammation, corneal regeneration, drug release and kinetics, angiogenesis and wound healing, respectively. According to Ramírez et al. [96] type I collagen hydrogel extracellular vehicles (EVs) with Apis mellifera royal jelly displayed effective wound healing to stimulate mesenchymal stem cell (MSC) migration and inhibition of biofilm formation by Staphylococcus aureus along with stable release kinetics up to 7 days. Curcumin crosslinked collagen aerogel system expressed the enhanced physical and mechanical features and controlled anti-proteolytic and pro-angiogenic potential, made them appropriate 3D scaffolds for medicine purposes. Here, curcumin as a nutraceutical was used as a crosslinker for further usage [97]. In a study by Chuysinuan et al. [98], gelatin-based hydrogel was prepared by mixing gelatin with GTA crosslinker and essential oil of Eupatorium adenophorum and applied on patients with open wound to assess the wound healing and anti-bacterial properties by analyzing release profiles.
Collagen-based composite materials with synthetic (CMC, PVA, PCL, PEMA, HEMA, polyurethane (PUR) etc.) or natural (CL, bacterial cellulose (BC), CHS, ALG, HA, GAGs etc.) polymers have major roles in biomedicine. Liu et al. [46] developed a composite of collagen-ALG with suitable mechanical strength and optical clarity to support human corneal epithelial cell growth using bovine serum albumin (BSA) as a model drug. The hydrogel system could be applied as therapeutic lens in patients with corneal illnesses. Collagen-based hydrogel preparation by mixing of acrylamide and 2-hydroxy ethyl methacrylate (HEMA) was used as DDS for linear release profile of gallic acid (GA) and naproxen up to 36 hours for wound healing. Addition of metal NPs such as Ag and Cu in this collagen-HEMA hydrogel films showed antimicrobial potential against Escherichia coli, Bacillus subtilis and S. aureus [29]. Bettnini et al. [99] prepared the porous collagen-based hydrogel scaffold with iron oxide (Fe3O4) NPs for the release of fluorescein and biocompatibility, cell viability of 3 T3 fibroblasts cells and proposed the safety and applications in tissue engineering and drug delivery. Reis et al. [100] developed the collagen-CHS thermoresponsive hydrogel conjugated with angiopoietin-1 derived peptide glutamine-histidine-arginine-glutamic acid-aspartic acid-glycine-serine peptide (QHREDGS) for the survival and maturation of cardiomyocytes. Hydrogels with high peptide load showed better morphology, viability, metabolic activity, success rate of beating as compared to hydrogels with low peptide concentration and control groups.
Graphene oxide (GO) sheets were inserted into the collagen-based hydrogels for the controlled release of fibroblast growth factor (FGF)-2 to induce pluripotent stem cell culture. Low permeability of GO sheets allowed the release of FGF-2 in controlled and regulated fashion while the FGF-2 interacted with collagen through electrostatic forces and partial hydrogen bonding. The release profile of FGF-2 was attained up to 400 hours using three different concentrations of GO and showed the fabricated hydrogel for better release of growth factors (GFs) for biomedical application [102]. Choi et al. [103] developed the collagen-TA-poly ethylenimine (PEI) hydrogel with layer-by-layer self-assembled films to overcome the problem of poor mechanical strength and fast release of inserted drug. Doxorubicin (DOX) was used as model cancer therapy drug. The multifunctional hydrogels showed sustained and controlled release up to 6–7 days without any cytotoxic effects along with antibacterial property against Gram positive and negative bacteria and higher strength to compression load.
Injectable hydrogels are the promising materials for cancer treatment and controlled delivery. With the minimal invasive processes injectable hydrogels can be located and remained at required position and also mitigate the irregular shape defects after the implantation. Aqueous injections of hydrogels could be used in biomedicine field such as drug release, wound healing, repair, tumor treatment, tissue regeneration, ocular/retinal disorders and cancer therapy etc. Fan et al. [115] designed the hydrogel prepared from tilapia skin collagen and CHS for the delivery of model nanobodies- 2D5 and KPU. The hydrogel was biodegradable and expedited the release of nanobodies and could pave the way for tumor treatment. Carboxymethyl cellulose (CMC)-collagen based aqueous injectable hydrogel showed promising antioxidative and drug carrier benefits to treat the retinal ischaemia or reperfusion injury in rat models and could be applied for drug based treatment of retinal illnesses in humans. Animals were treated with interleukin (IL)-10 loaded hydrogels and expressed better therapeutic results of restoration of retinal structures and reduced retinal apoptosis, significantly decreased retinal oxidative stress in comparison to control group [52].
4.2 Films/membranes
The films or membranes are very thin and flexible layer of biopolymers with or without plasticizer having optical and mechanical anisotropy with very high tensile strength making them suitable for various medical applications of sustained drug release, cell adhesion, proliferation, differentiation, cancer treatment, wound healing and tissue regeneration. The thin films are the prominent material to target sensitive locations not possible with other formulations like liquid or tablets [226]. Thin films exhibited the improvised onset of drug activity, decreased dose quantity or frequency and augmented drug efficacy, reduced side effects by drug and extensive metabolism [227, 228].
Gil et al. [122] developed the innovative chromium free-collagen film for slow drug release carrier for skin burn related complications like ulcers and infected wounds. The biocompatible films were tested for drug silver sulfadiazine and its antibacterial potential against Pseudomonas aeruginosa, E. coli, Micrococcus luteus, S. aureus, Proteus vulgaris and Klebsiella pneumoniae. The findings proposed the effective strategy for Chromium (Cr) removal from leather waste and generation of environment friendly material could be transformed into collagen films, promising candidate for drug carriers. The use of biocompatible, recyclable, biodegradable natural materials has become tremendously increased in recent decades. Langasco et al. [123] developed the natural collagen films from marine sponges for topical drug delivery application. L-cysteine loaded films were analyzed for different drug concentrations and drying parameters. The films showed the healing potential of cysteine, acted as biocompatible carrier to absorb excess of wound exudate along with drug release. The films could be the promising material and might behave as bioactive, biomimetic drug carrier for effective wound healing. Jana et al. [130] synthesized the fish scale collagen-carboxymethyl guar gum film loaded with broad spectrum antibiotic ceftazidime. Around 90–95% of ceftazidime was released after 96 hours at physiological pH. In vitro study on NIH 3 T3 fibroblast cell line showed the biocompatibility of crosslinked film and antibacterial results exhibited the inhibition of S. aureus and P. aeruginosa.
Collagen-CHS based films/membranes are important biomaterials and used for antibiotic release, wound healing, cancer treatment, transdermal delivery, cardiac illness, tissue engineering. Martino et al. [132] formulated the collagen-CHS film for the delivery of mixture of local anesthetics compounds- lidocaine, tetracaine and benzocaine. The films were developed by rapid, cost effective and highly reproducible casting approach. The films showed good mechanical strength and flexibility with high water permeability. The anesthetics were uniformly distributed in the film and controlled released from 6 to 24 hours. The film exhibited in vitro non-cytotoxicity, cell proliferative and biocompatibility properties against human dermal fibroblast cells making it better candidate for drug release and proliferation. Liu et al. [136] fabricated the collagen-CHS-GO composite film using EDC as crosslinker loaded with basic FGF for effective wound healing through controlled release. The film had improved thermal endurance and higher degree of crosslinking for advanced mechanical strength due to GO. This novel DDS prevented the initial sudden release and loss of bioactive potential of basic FGF in vivo and in vitro. In cultured L929 fibroblasts, the film showed good biocompatibility in terms of cell adhesion and proliferation. These films were implanted on rats showed the wound remodeling to repair full thickness skin wound. So these films were promising substitute as wound dressing material for drug delivery with wound healing. Daja et al. [27] developed the collagen/PVA anionic membrane for drug carrier of ciprofloxacin hydrochloride along with antibacterial efficacy and its application in the treatment of ulcerative keratitis. The membrane provided the sustained DDS and inhibited the growth of S. aureus and E. coli during 48 hours. The membrane had proper mechanical strength, water amount, hydrophilicity, permeability and pH without any stress to cornea during interaction. The collagen fibrils in membrane decreased stromal damage and improved the epithelium regeneration. The formulated membranes were cost-effective and secured biomaterial for the treatment of corneal ulcers in patients.
4.3 Scaffolds/sponges/matrices
Scaffolds are collagen sponges or matrices with three dimensional network structures. Scaffolds can be obtained with various synthesis approaches of freeze drying, electrospinning and 3D printing etc. The freeze drying is the most effective method preserving the structure and native or inherent properties of collagen along with loaded drug/active principle in the scaffold. Collagen-based scaffolds or matrices are the important and favorable materials for bone, skin and tissue regeneration, angiogenesis, gene delivery, wound healing and repair, sustained drug release and improved gene expression. Now a days several commercially available collagen-based sponges in the market are Collarx®, Collatamp® G, Collatamp®EG Sulmycin® Implant, Garamycin® Schwamm, Duracol®, Duracoll®, Gentacol®, Gentacoll®, Garacol®, Garacoll® and Cronocol® - Gentamicin surgical implants.
Elangovan et al. [141] developed the non-viral gene delivery system for bone regeneration with the help of collagen scaffold to deliver the PEI-plasmid DNA encoding platelet derived growth factor (PDGF)-B complexes. The complexes expressed low cytotoxicity and markedly higher proliferation of human bone marrow stromal cells in contrast to scaffold without DNA and PDGF-B. In rats model the complexes exhibited higher bone volume followed the 4 weeks of grafting in comparison to empty scaffolds. The results advocated the use of non-viral scaffolds for bone regeneration along with gene delivery vehicle in clinical applications. Collagen-based biopolymers are one of the most important biomaterials to formulate the matrices in the field of tissue engineering due to significant non-toxicity, biocompatibility and resorptive potential. López-Noriega et al. [150] designed the collagen-hydroxyapatite (HAP) scaffold with covalently attached thermoresponsive liposomes. The encapsulated drug with pro-osteogenic and anti-osteoclastic properties was PTHrP107–111, a pentapeptide. The regulated release of pentapeptide was correlated with enhanced expression of osteopontin and osteocalcin genes in cultured pre-osteoblastic MC3T3-E1 cells. This scaffold medicated drug release and cell regeneration has vast potential for various types of tissue regeneration.
Collagen-based 3D biomaterials are broadly used in the field of biomedicine for their properties of biocompatibility, inherent bioactivity to induce cell proliferation, hemostatic and low antigenicity. A porous and highly structured biomaterial such as sponges or matrices promotes the flexibility, permeability and biomimicry [229, 230]. Crosslinking or amalgamation of natural or synthetic biopolymers improvises the shortcomings of collagen polymer alone in terms of physico-chemical and biological parameters. Alagha et al. [166] prepared the porous muco-adhesive collagen-CHS bio-sponge as DDS for dexamethasone to treat the oral mucositis. The sponge was characterized by X-ray, FTIR, SEM, DSC and swelling behavior. The collagen-CHS sponge showed regulated drug release up to 10 hours as compared to collagen sponge for 5 hours. David et al. [168] fabricated the collagen-PCL-HA macroporous sponge to deliver the model drug methylene blue and curcumin. Several parameters such as absorption, water uptake, drug loading and delivery along with mechanical and structural features were examined for the developed sponge. In comparison to control group, the sponge showed sustained release kinetics for drugs and making the sponge as future material for applications of wound dressing and lab models.
Collagen matrices are able to deliver the gene or plasmid DNA in cultured cells and alter the gene expression in tissue engineering. Orsi et al. [171] formulated the bio-activated collagen-PEI-DNA complex to control the gene expression and attract the specific cell type. The transfected NIH3T3 cells with matrix-PEI-DNA complex secreted the plasmid encoded protein to promote the tissue repair and regeneration. The developed matrix could be the new approach for tissue repair.
4.4 3-D microspheres/ microparticles/micro-beads
Microspheres, microparticles or micro-beads are spherical particles with large surface to volume ratio for improved drug delivery, growth factors and broad surface area for cellular interactions to other biomolecules [28]. The size of collagen-based microparticles ranging from 3 to 40 μm. Berndt et al. [231] developed the collagen microspheres encapsulated astrocytes crosslinked with poly (ethylene glycol) tetrasuccinimidyl glutarate (4S-StarPEG) as growth enhancing and carrier for injured spinal cord. Astrocytes were transfected with plasmids encoding nerve growth factor (NGF)-ires-enhanced green fluorescent protein (EGFP) genes and then added to the culture of rat dorsal root ganglion and significantly improved growth was observed. The report showed the potential of microspheres as carrier of astrocytes for neural tissue regeneration. Zhang et al. [53] formulated the 3-D microsphere of collagen-BC-bone morphogenic protein (BMP)-2 for bone tissue augmentation. The 3D microporous microspheres effectively enhanced the adhesion, proliferation and osteogenic differentiation of mice MC3T3-E1 cells and expressed adequate biocompatibility.
Marine based collagen from jellyfish species Catostylus tagi was used to develop the microparticles formulation for sustained delivery of lysozyme and α-lactalbumin. The collagen microparticles were crosslinked with EDC and investigation of lysozyme activity was retained throughout the crosslinking and encapsulation process. These microparticles from marine collagen could be the promising material for controlled release of therapeutic proteins [186]. Yang and Fang [232] developed the microporous nano-HAP/collagen/phosphatidylserine scaffolds embedding collagen microparticles for the sustained release of steroidal saponins for bone tissue engineering in cultured MC-3 T3-E1 cells. The scaffolds provided scope for spatial and temporally controlled drug delivery and deposition at wounded site and reduction in adverse side effects. Vardar et al. [190] formulated the novel injectable collagen-fibrin microfluidic system loaded with recombinant insulin like growth factor-1 (α2PI1–8-MMp-IGF-1) to treat the urinary incontinence. The natural crosslinker genipin was used for collagen modification. The microbeads showed slow release of GF and positive cell behavior for the induction of in vivo smooth muscle regeneration for effective management of urinary incontinence.
4.5 Nanoparticles/ nanocomposites/nanofibres
Nanomaterials within the size of 1–100 nm are one of the best materials with admirable biochemical and pharmacological attributes [233]. Biological protein-based NPs are applied in different applications due to eco-friendly nature and biocompatibility and replacing the synthetic materials. Collagen is the preferred NP substance and by direct or indirect crosslinking to collagen NPs provide better substitute for protein based drug delivery vehicle [234]. The crosslinking of collagen with NPs is the new strategy to enhance the mechanical and physical strength of collagen tissue for various applications. Metal oxide NPs such as iron oxide (Fe3O4), zinc oxide (ZnO), alumina oxide (Al2O3), tantalum oxide (TaO), Al2O3-ZrO2 and Fe3O4-ZnO improve the mechanical features of collagen-based biomaterials [99, 195, 235]. The metallic NPs provided broad spectrum antimicrobial, antioxidative and anti-inflammatory attributes [236, 237] to collagen based material and serve as an alternative to toxic chemical crosslinkers and impede the collagen degradation by physical crosslinking. These features advertise the use of NPs based collagen biopolymers in medical field such as targeted controlled drug delivery, cell targeting and tissue engineering. Choi et al. [195] prepared the collagen hydrogel containing the ferritin NPs, TaO NPs along with transforming growth factor (TGF)-β1 for the controlled release and imaging medium for regeneration of oral tissues.
NPs based biopolymers for cancer therapeutics are effectively utilized in recent years due to targeted and controlled release kinetics. Anandhakumar et al. [193] fabricated the collagen peptide-CHS NPs for encapsulation of standard cancer drug DOX in cancer therapy. The NPs showed high encapsulation capacity of DOX and pH regulated release. NPs with DOX expressed significant anti-proliferative activity against HeLa cells in contrast to normal cells. The NPs showed excellent biocompatibility with high power as smart DDS for cancer therapeutics. Zhang et al. [47] designed the collagen-ALG biocomposite doped with silver NPs (AgNPs) with antibacterial potential and applicable as wound dressing. The biocomposite exhibited insignificant in vitro toxicity at lower concentrations of AgNPs and also inhibited the growth of S. aureus and E. coli. Saska et al. [197] fabricated the nanocomposite of BC-collagen-apatite and osteogenic growth peptide (OGP) for bone tissue regeneration. The OGP containing nanocomposite triggered the early development of osteoblastic phenotype and elevated cellular growth without any cytotoxic, genotoxic or mutagenic adverse effects. The nanocomposite could be the promising future biomaterial for bone tissue engineering.
4.6 Inserts/shields/monolithic devices or pellets
The approach of applying ocular collagen inserts to administer the drug for prolonged period was started in early 1970s. The inserts were films or as molded rods or wafers of collagen incorporated with drug such as pilocarpine, penicillin-procaine, erythromycin, erythromycin esolate and gentamicin etc. in the form of eyedrops, ointments and subconjunctival injections to treat the cornea related disorders [200, 201, 202]. In the late 1980s researches on inserts were overtaken by shields which became commercially available in the market in reproducible manner [7].
Collagen shields were formulated as corneal bandages/dressings to facilitate the wound healing, allow sufficient oxygen transmission, lubricate the eye surface to minimize stress and to regenerate the corneal epithelial linings after corneal injury or damage, transplantation, radial keratomy, glaucoma, keratitis or cornea related disorders [238, 239]. These shields could be used as carrier to deliver the ophthalmic medication such as water soluble antibiotics- gentamicin, vancomycin, tobramycin, netilmicin, polymyxin B sulphate, trimethoprim, amphotericin B, pilocarpine and flurbiprofene sodium etc. [7]. The drug delivery aspect of shields is limited by transparency, reduced visual acuity, slight irritation, complex administration procedure and prolonged durability. In current scenario, the commercial formulations like Biocora®, ProshieldO®, MediLenso®, Irvine® and Chiron® etc. are showing better future for delivery of corticosteroids and subconjuctival antibiotics etc. [240].
Collagen minipellets are cylindrical injectable controlled release drug delivery vehicle. In 1992, Takeuchi [211] prepared the little rods of 1 mm in diameter and length of 15 mm of injectable collagen minipellet for the local delivery of minocycline and lysozyme to treat periodontitis. Fujioka et al. [241] used the injectable collagen minipellet to deliver interleukin (IL)-2 molecule. Maeda et al. [242] used the collagen minipellet as a carrier to deliver the recombinant human bone morphogenic protein (rhBMP)-2 to induce the bone formation in mice models. Lofthouse et al. [243] developed the degradable collagen minipellet infused with avidin and IL-1β as vaccine carrier for clostridial antigen into sheep and mice. Higaki et al. [244] fabricated the biodegradable collagen minipellet to deliver the tetanus and diphtheria toxoid as single dose vaccine delivery system in mice.
Protein-based biomaterials have excellent biocompatibility with minimal cytotoxicity and biodegradability and theirs physical, chemical and biological parameters can be altered according to biomedical application. Collagen, a major protein in animal body is the attractive biopolymers for the delivery of therapeutic drugs, growth factors, hormones, proteins/enzymes, gene and imaging probes in the field of drug delivery systems, wound healing, bone grafts, implants, tissue regeneration, ocular diseases, cosmetic surgery, reconstructive surgery and cardiac treatments.
The researchers are consistently designing the protein-based hybrid materials with desired physical, mechanical, chemical and biological properties. Collagen-based hybrid biomaterials can be formed with natural polymers like CHS, CL, ALG, gelatin, HA, CHD, HAP or the chemically modified form of these natural polymers or with synthetic polymer such as CMC, PVA, PCL, PEMA, PLA and PLGA etc. through various physical, chemical and enzymatic crosslinking approaches. Collagen-based biomaterials can be fabricated into variety of physical forms hydrogel, films or membranes, scaffolds or sponges, matrices, 3-D microspheres, microparticles, nanoparticles, nanocomposites, inserts, shields and pellets for drug based delivery of synthetic and natural active biocomponents in various fields of medical science. Collagen-based biomaterials have attracted the researchers to develop efficient and controlled therapeutic vehicles for clinical applications ensuring the patient compliance. The more efforts are needed to translate the clinical results into production scale with collaboration of researchers, material scientists, clinical doctors and industry.
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Written By
Amit Kumar Verma
Submitted: 22 January 2022Reviewed: 04 February 2022Published: 04 July 2022
Open access peer-reviewed chapter
