# Collagen Nanoparticles in Drug Delivery Systems and Tissue Engineering
## 1 Introduction  
Collagen is an abundant protein found in the human body existing in bones, tendons, muscles and skin [1]. Properties such as tensile strength, biodegradability, notable stretchability, absorption in-vivo capacity, biocompatibility, biomimetic nature, weak antigenicity, and remarkable safety profile make it a significant element in applications of drug delivery systems (DDS) and tissue engineering (TE) [2]. Collagen has good in vivo absorption, synergism with bioactive materials, haemostatic characteristics, and low immunogenicity [3, 4]. To overcome limitations such as enzymatic degradation, weak mechanical strength and low thermal stability, methods such as crosslinking, grafting polymerization, blending and covalent conjugation are adopted, resulting in biomaterials of discrete physical forms such as shields, films, sponges, hydrogels, microspheres, sheets, coatings, liposomes, disks, nanofibers, tablets, pellets and nanoparticles (NPs) [5, 6]. Collagen acts as an efficient carrier for the delivery of various agents such as genes, drugs, proteins and growth factors. It is possible to alter collagen to fabricate materials of various duraibilities, structures and forms due to its adaptable nature. Collagen can also form complexes with different biologically active and medical substances [7]. Some of the applications of collagen are the formation of microspheres and microneedles for drug delivery [8], formulation of NPs for gene delivery [9], development of pellets and tablets for protein delivery [10], formation of gels and combination with liposomes for sustained drug delivery [11], cancer treatment [12] and collagen shields in ophthalmology [13]. The collagen types that can be purified and isolated for usage in pharmaceutical industries for drug delivery are: (i) Enzyme and alkali treated collagen, (ii) natural salt-soluble collagen,(iii) insoluble collagen and (iv) acid-soluble collagen [14]. The degradation of collagen-based biomaterials for TE applications could possibly lead to tissue functionality and structure restoration. A few applications of collagen in TE have been utilised in cornea and skin related treatments [15; 16; 17], osteochondral defects [18], wound dressing, dermal filler and delivery systems [17]. Collagen-based wound dressings are used for applications of wound and burn coverage, ulcer treatment, therapeutic enzyme immobilization, antithrombogenic surfaces and bone filling substances [3]. When combined with elastic which provides flexibility, collagen supports and provides firmness and strength to body tissues and organs [18]. The usage of collagen as skin substitutes led to its usage in bioengineering of tissues such as ligament and blood vessels [19]. Particles with diameters 1-100 nm are called NPs. DDS based on NPs display enhanced efficacy of drugs and improve the drug's half-life, hydrophobic drug solubility and controlled and sustained drug release in the infected regions. Stimuli-responsive NPs regulate drug biodistribution and reduce drug toxicity [20; 21]. TE requires the local controlled delivery of these bioactive and contrast compounds to deploy control over and monitor the tissues that are engineered. This need of TE is satisfied by NPs as they control scaffold characteristics such as mechanical strength and yield regulated release of bioactive compounds [22; 23]. NPs overcome limitations such as unstable bioactivity, reduced half-life of bioactive and contrast compounds and low solubility, which makes them favourable for bioactive compound delivery and monitoring applications such as specific site imaging, cell patterning, biosensing, DNA structure probing and detection of molecules [23; 24; 25]. Polymeric NPs possess reduced cytotoxicity, high permeation and retention (EPR) effect, good biocompatibility and are able to deliver drugs which are poorly soluble and also control their release.