Functional Bio-based Materials for Regenerative Medicine: From Bench to Bedside (Part 1)

The skin is known as the largest organ in the human body as it functions to regulate the temperature in the human body and acts as the first-line defence. The skin consists of two layers: the epidermis (the outer layer of skin) and dermis layers (the inner layer of the skin) occupied by specific skin cells. Whenever the skin barrier is compromised, the skin heals following four phases: haemostasis, inflammation, proliferation, and remodelling. Wound healing takes a few weeks for acute wounds, however it takes a longer period to heal chronic wounds. Chronic wound complication extends the inflammation phases during the wound healing process and becomes a significant problem in the healthcare field. Therefore, various treatments were produced to reduce the healing time in chronic wounds and produce less scarring. Acellular treatments have gained attention in wound healing research as these treatments have a lower risk of rejection and are easily obtained through nature or lab. Acellular treatments include growth factors, bioactive molecules, and peptides that are clinically proven to have faster healing time and reduce scarring as these treatments are readily available in the market. Biomaterials have become a novel study in wound healing research due to their vast potential as alternative treatments for skin wound healing. Therefore, the chapter discussed the acellular strategies for tissue wound healing. 

The development of biomaterials in tissue engineering has already started decades ago. A wide variety of biomaterials are being used as alternatives in clinical applications. Lately, animal by-products have increased in demand for natural substrates in various sectors. As in tissue engineering, animal-based biomaterials are from different resources or origins of animal species that are being studied and applied for disease treatments. In addition to this, novel biomaterials are being produced that could imitate the physiology of natural healing mechanisms or the regeneration of certain tissues. Thus, the efficiency in utilising animal by-products could alleviate the waste management cost and scarcity of materials, which could reduce environmental pollution. This book chapter discusses different classifications of animal byproducts, their unique characteristics, and the advantages of these products that could embark as new alternative approaches for treating diseases. 

Chitosan is a unique polymer owing to its cationic property that allows interactions with various biological entities and is subsequently produced into novel functional products for biomedical applications, including tissue regeneration. Its cationic nature is conferred by amino groups present in its structure that are also responsible for various properties, including antibacterial activity. Chitosan is a biomaterial that has been extensively used in tissue engineering due to its ability to facilitate three-dimensional (3D) cell growth and proliferation as well as organize the deposition of collagen, the important processes in wound healing. Moreover, chitosan is a biocompatible and biodegradable polymer, making it an outstanding material for tissue engineering applications. Besides, chitosan possesses biological or pharmacological activities such as hemostatic, antioxidant, antimicrobial, and antiinflammatory, further expanding its biomedical applications. In tissue engineering, chitosan has been developed as scaffolds in the form of membranes, sponges, nanofibers, and hydrogels for treating various tissue damages. They are used to provide a suitable environment for supporting the growth of cells. In combination with nanotechnology, chitosan is converted into nanoparticles that possess unique properties and hence, they have been utilised in wound healing, cartilage, and bone regeneration. This chapter highlights the roles of chitosan-based nanoparticles in tissue regeneration along with their recent developments. 

Cell adhesion is a complex mechanism that involves a dynamic interaction between the cell surface protein and specific ligands. It has become a crucial part to be understood when it comes to cell adhesion to biomaterial, especially in the tissue engineering field. In this chapter, we narratively discussed the basic principle of cell adhesion and the factors that affect this process. The characterisation of cells on biomaterials has also been discussed, as well as their application in the tissue engineering context.

Regenerative medicine (RM) is a field of study that helps repair or restore native tissue function which has lost its functionality due to chronic diseases and trauma. The regeneration process can be promoted by constructing biomimetic systems, which can support cellular growth and proliferation. In this regard, the development of injectable hydrogels has gained enormous attention in recent times. An arrangement of cells and bioactive molecules in the three-dimensional extracellular matrix created by injectable gels is favorable for the regeneration of damaged tissues. Ideally, the injectable hydrogel remains in the solution form before injection and rapidly undergoes gelation at the physiological condition. A high water content, mechanical strength, scope of improved functionalization, injectability, and ease of implantation make the injectable hydrogel an ideal candidate for tissue-specific repair. This chapter aims to concisely summarize the mechanism and recent fabrication advancement of the injectable hydrogel that is being used in RM applications. A vast number of injectable hydrogels have been discovered for bone, cartilage, skin, and cardiovascular tissue regeneration, which are discussed in detail in the chapter. In gist, it is expected that injectable hydrogels will become a promising tool for a variety of tissue repair applications shortly.

Diabetes is a metabolic disorder characterised by long-term hyperglycemia caused by insulin resistance [1]. According to scientific studies, the number of people with diabetes climbed from 30 million in 1985 to 177 million in 2000 and is expected to increase to 552 million by 2030 [2, 3]. Diabetic patients suffer from impaired or delayed wound healing due to a few factors leading to the development of chronic wounds. Chronic wound management is becoming an economic burden on the healthcare system. With the rising prevalence of chronic diabetic wounds, finding effective treatment strategies and advancing therapy are critically important. Although the exploration of electrostimulation therapy for wounds is only very recent, it is a promising approach to expedite wound healing. With recent advancements in wearable device technology, a new treatment strategy that integrates electrical stimulation and biomaterial dressing has been adopted.

The utilisation of bio-based materials in constructing an advanced wound dressing for regenerative medicine is not new. Due to the fundamental principle of tissue engineering in regenerative medicine, bio-based wound dressing formulated from by-products or animal or plant wastes could contribute significantly to healing processes. Bio-based materials help to regenerate and replace damaged tissues and shorten the recovery period without frequent dressing changes. The bio-based dressing development begins with a small-scale benchwork that focuses on modifying and treating the bio-based material before it is clinically applied for wound treatment procedures. The modified bio-based materials then turn into functional wound dressing in various forms such as hydrogel, membrane, sponges, film, or fibres. The dressing’s therapeutic healing properties can be enhanced by subjecting it to physical, chemical, and biological treatments. The dressing principle must abide by tissue engineering needs and offer a broader range of alternatives that can clinically treat different types of wounds based on different etiology. Therefore, this book chapter highlights the advantages of a bio-based material and its modification for wound dressing for tissue engineering purposes in regenerative medicine.

The utilization of nanoscale biomaterials in various fields of modern science has shown great change and benefits in this present era. Due to their unlimited potential, many researchers have focused on further studies, and today, they play a good role in human health improvement programmes. Accordingly, it is true that the use of nanomaterials in tissue engineering is one of the most advanced technologies in medical care. The technology which integrates materials science and engineering with biology in order to improve the induction of tissue regeneration is called tissue engineering. This technology helps in controlling the cellular combined with synthetically engineered materials and is used for various treatments. One of its main functions is the treatment of structurally degenerated organs in the human body. Tissue engineering techniques can be upgraded with distinct properties of nanomaterials like better adaptability, good response, delivery potential, and better controllability. Moreover, unlike other materials, they are highly efficient, reliable, and easily decompose. Depending on the type of application, different kinds of nanomaterials are used, such as polymers, metals, ceramics, and their various compositions. Consequently, it can be assumed that the approaches of incorporating nanomaterials in tissue engineering will enhance the disciplines of tissue regeneration.

 Regenerative medicine focuses on replacing injured tissues and organs by utilising biophysical and biochemical cues to develop bioscaffolds suitable for regenerating damaged or injured tissues. The scaffold has an important role in guiding the development of the regenerative process that allows the migration and attachment of cells and, to a certain extent, becomes the source of nutrients influencing the cells or tissue's biological mechanism. Hence, the selection of biomaterials is important to ensure biocompatibility and suitable mechanical properties for tissue engineering. Different sources and types of biomaterials can be used in the fabrication of scaffolds, including composites. Composite biomaterials consist of more than one material with different morphologies and compositions, causing it to become multiphased, which can ameliorate the scaffold’s mechanical properties, flexibility, and structural properties to ensure a suitable microenvironment for cell growth and viability. Nevertheless, biocompatibility issues need to be addressed, particularly with synthetic materials, which led investigators to explore other sources and types, such as plant-based biomaterials, to fabricate suitable and safer composites. Aside from being more sustainable and perhaps more eco-friendly, plant-based composite materials fulfill the criteria required for biomaterials and exhibit many advantages that can be adapted in their fabrication techniques. Hence, in this chapter, the advantages and development of plant-based materials will be discussed, focusing on the potential of oil palm and konjac plants as sources of biomaterials

The skin regulates several important physiological processes which have a significant clinical influence on wound healing. Tissue-engineered substitutes may be used to help patients with skin damage to regenerate their epidermis and dermis. Skin replacements are also gaining popularity in the cosmetics and pharmaceutical sectors as a viable alternative to animal models for product testing. Recent biomedical advances, ranging from cellular-level therapies like mesenchymal stem cell or growth factor delivery to large-scale biofabrication techniques like 3D printing, have enabled the use of novel strategies and biomaterials to mimic the biological, architectural, and functional complexity of native skin. This chapter elaborates on some of the most recent methods of skin regeneration and biofabrication that use tissue engineering techniques. Current problems in manufacturing multilayered skin are discussed, as well as opinions on attempts and methods to overcome such constraints. Commercially accessible skin substitute technologies are also investigated, as an effort to mimic native physiology, the function of regulatory authorities in facilitating translation, and current clinical requirements. Tissue engineering may be used to develop better skin replacements for in vitro testing and clinical applications by addressing each of these viewpoints.

Tissue replacement using engrafting biomaterials or artificial organs to restore lost functions post-injury is one of the leading regenerative medicine practices. The last two decades witnessed the emergence of many promising biofabrication approaches such as bioprinting. However, bioprinting allows the placement of complex structures that are multi-layer (using hydrogel biomaterials), multicellular, vascularized, and multifunctional. Different bioprinting approaches are being developed and used to print hundreds of promising bioinks combinations into tissue-specific niches to grow living organs for translation, disease modelling, and drug delivery. This book chapter reviews the three primary bioprinting techniques with their advantages and limitations. Moreover, this chapter discusses the natural and synthetic biomaterials and the additives and crosslinking methods used to fabricate functional bioinks that boost cell growth, proliferation, migration, differentiation, and homeostasis.

Platelet-rich plasma (PRP) is a well-established biological product used in the tissue engineering field to promote wound healing and tissue regeneration. PRP can form platelet gel with the addition of thrombin and/or calcium salts. Nonetheless, PRP is more commonly combined with biomaterial and cells for various tissue engineering applications. Over the years, PRP has been used in the dermatology field for hair follicle regeneration and wound healing, in the orthopaedic field for bone, muscle, tendon, and ligament repair, and in dentistry for many dental procedures, including dental implants. Despite the long historical use of PRP in the clinic, the PRP isolation technique is still continuously changing, evolving, and improving to increase the therapeutic effect of PRP. Nowadays, PRP is not only used as a biomaterial but it also can be used to replace foetal bovine serum and human serum in primary cell culture, especially for cell therapy purposes. PRP derivatives such as platelet lysate, plateletderived growth factors, and platelet-derived extracellular vesicles also are precious functional materials used clinically in the tissue engineering field. In this book chapter, we review the different subclasses of PRP, including its derivatives, its research, and clinical applications, and underline the challenges of PRP in clinical translations.

Nanotechnology is a greatly advancing field of scientific research due to its largely untapped potential, which may apply to various clinical uses. This book chapter focuses on the potential use of nanocollagen, graphene, and antibiotic components in biomaterial fabrication for wound healing. Nanocollagen is simply regular collagen broken down to the nanometer scale. Its nanocollagen-based biomaterials also conform to the ideals of tissue engineering, which are excellent biocompatibility with a high bioabsorption rate and little to no antigenicity while having an extensively cross-linked structure suitable for cellular growth and metabolism. Nanocollagen can be fabricated through electrospinning, nanolithography, self-assembly, and others. The physiology of wound healing follows specific proceedings, which are haemostasis, inflammation, and remodelling stages. The wound healing process may be improved through the use of nanocollagen biomaterials, together with the addition of graphene and antibiotics. Nanocollagen biomaterials aid in acting as a barrier for the wound against infections while providing collagen in the nanoscale to accelerate healing. The addition of antibiotics into the nanocollagen biomaterial aids in preventing bacterial infection by the inhibition of biofilm formation. Graphene, specifically in its oxide form, also acts as an antibacterial agent while potentially providing mechanical durability to the biomaterial scaffold. Along with the benefits of graphene oxide application in wound healing, its challenges are discussed in this book chapter. With that, this book chapter suggests the beneficial combinatorial factors of nanocollagen, graphene, and antibiotics that can potentially produce biomaterials with strong antibacterial properties while accelerating wound healing.

Skin tissue engineering requires a multidisciplinary effort, reflecting the complexity of the organ that it attempts to replace after loss due to injury, trauma or as a consequence of diseases. Skin substitution aims to achieve complete closure of the existing defect and restoration of the normal function of the tissue. The major challenge faced whilst attempting to achieve such outcomes is successfully recapitulating the complex biology, chemistry and mechanical environments within native skin. Although major advances have been made to include biological entities (cells, biomolecules, small molecules) into engineered substrates to promote biological responses, the role that the substrate itself provides is often overlooked. In this chapter, we consider what might be required so that successful skin substitution post-trauma can be routinely achieved. This will require that researchers from different disciplines collaborate to ensure that not only should the cell types and matrices be carefully chosen, but in parallel, the resultant mechanical parameters need to be considered in the design process. We postulate that an engineering approach is required to recapitulate the skin by driving native healing pathways, ultimately creating a system where the synergistic effects are greater than simply the sum of its parts; where each partial component reflects various aspects of the human biology (cells, annexal structures, etc.), chemistry (materials, gradients, etc.) and physics (mechanics, etc.).