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    Nanotechnology Applications for Tissue Engineering
    Nanotechnology Applications for Tissue Engineering
    Nanotechnology Applications for Tissue Engineering
    Ebook736 pages7 hours

    Nanotechnology Applications for Tissue Engineering

    By Sabu Thomas

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    Tissue engineering involves seeding of cells on bio-mimicked scaffolds providing adhesive surfaces. Researchers though face a range of problems in generating tissue which can be circumvented by employing nanotechnology. It provides substrates for cell adhesion and proliferation and agents for cell growth and can be used to create nanostructures and nanoparticles to aid the engineering of different types of tissue. Written by renowned scientists from academia and industry, this book covers the recent developments, trends and innovations in the application of nanotechnologies in tissue engineering and regenerative medicine. It provides information on methodologies for designing and using biomaterials to regenerate tissue, on novel nano-textured surface features of materials (nano-structured polymers and metals e.g.) as well as on theranostics, immunology and nano-toxicology aspects. In the book also explained are fabrication techniques for production of scaffolds to a series of tissue-specific applications of scaffolds in tissue engineering for specific biomaterials and several types of tissue (such as skin bone, cartilage, vascular, cardiac, bladder and brain tissue). Furthermore, developments in nano drug delivery, gene therapy and cancer nanotechonology are described. The book helps readers to gain a working knowledge about the nanotechnology aspects of tissue engineering and will be of great use to those involved in building specific tissue substitutes in reaching their objective in a more efficient way. It is aimed for R&D and academic scientists, lab engineers, lecturers and PhD students engaged in the fields of tissue engineering or more generally regenerative medicine, nanomedicine, medical devices, nanofabrication, biofabrication, nano- and biomaterials and biomedical engineering.

    • Provides state-of-the-art knowledge on how nanotechnology can help tackling known problems in tissue engineering
    • Covers materials design, fabrication techniques for tissue-specific applications as well as immunology and toxicology aspects
    • Helps scientists and lab engineers building tissue substitutes in a more efficient way
    LanguageEnglish
    PublisherElsevier Science
    Release dateJan 3, 2015
    ISBN9780323353038
    Nanotechnology Applications for Tissue Engineering

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      Book preview

      Nanotechnology Applications for Tissue Engineering - Sabu Thomas

      zeolites.

      Preface

      The proposed book focuses on the new technologies that are transforming modern medicine: nanomedicine, tissue engineering, and drug delivery. This book enlightens some of the recent progress in nanomedicine and tissue engineering. Future biomaterials must simultaneously promote tissue regeneration while minimizing immune responses and inhibiting infection. While the field of tissue engineering has promised to develop materials that can promote tissue regeneration for the entire body, such promises have not become reality. However, tissue engineering has experienced great advancement due to the recent emergence of nanotechnology. Specifically, it has now been well known that increased tissue regeneration can be achieved on almost any surface by employing novel nanotextured surface features. Numerous studies have stated that nanotechnology accelerates various regenerative therapies, such as those for the bone, cartilage, vascular, heart, bladder, and brain tissue. Various nanostructured polymers and metals have been investigated for their cytocompatibility. This book discusses several latest nanotechnology innovations in regenerative medicine as well as their relative levels of success.

      The book also covers the developments in nano drug delivery, gene therapy, and cancer nanotechnology. Nanoscale particles are being designed to improve drug bioavailability, a major limitation in the design of new drugs. It provides a conceptual framework that includes exposure to all the necessary background material in the field of regenerative medicine. Finally, it mentions about the toxicological considerations which need to be taken care of while handling nanoparticles and discusses different ways of minimizing the toxicity.

      Chapter 1

      Nanomedicine and Tissue Engineering

      C.K. Sudhakar¹, Nitish Upadhyay¹, Arpit Verma¹, Ankush Jain¹, R. Narayana Charyulu² and Sanjay Jain¹,    ¹Smriti College of Pharmaceutical Education, Indore, Madhya Pradesh, India,    ²Department of Pharmaceutics, NGSMIPS, Mangalore, Karnataka, India

      Nanomedicine drives the convergence of nanotechnology and medicine; it is delineated as the application of nanotechnology in healthcare. Tissue engineering is classified as an associate field of biomaterials and engineering. Merging the best of both worlds: nanomedicine and tissue engineering has great impact in human healthcare practice. Smart drug delivery systems (liposomes, dendrimers) that are incorporated within matrices (polymeric scaffolds and hydrogels) for tissue engineering approaches show sustained delivery of drugs from 3D matrices for tissue engineering. One major application of nanomedicine in medical field is the delivery of drugs to the damaged cells. Carbon nanotubes, dendrimers, and liposomes are important tissue engineering scaffold materials and drug delivery systems which deliver drugs to impaired tissues. Medical nanorobots which are rigid, biocompatible nanometer-scale materials can be used for improving tracking of cells, sensing of microenvironments, delivering of transfection agents, and scaffolding for incorporating with the host’s body. These molecular machines will be medicines of tomorrow.

      Keywords

      Nanomedicine; tissue engineering; drug delivery system; nanorobots; scaffold materials

      1.1 Introduction

      Nanoparticles were used by artisans during the ninth century in Mesopotamia to generate glittering effects on the surfaces of pots [1]. The advent of nanotechnology in medicine was initiated after Richard Feynman, a physicist, quoted the sentences There’s Plenty of Room at the Bottom [2]. Technological advances in the field of nanotechnology have led to the birth of a new field of study, nanomedicine, a blend of nanotechnology and medicine [3]. Nanotechnology in drug delivery has contributed several nanocarriers that have inimitable properties in biological system.

      1.1.1 Nanomedicine

      The main perception of nanomedicine is to formulate in such a way that it will occupy the small spaces in our body and target specific parts of body. Incorporation of nanoparticle into our body for treatment or prevention of disease is impossible in the past, but now researchers are keen to explore nanoscale medicine for the welfare of people. Nanomedicine may also escalate the effectiveness of pharmaceutical research. Nanomedicine may be defined as the monitoring, repair, construction, and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures [1,2]. It drives the convergence of nanotechnology and medicine (Figure 1.1). It is delineated as the application of nanotechnology in healthcare. Nanomedicine, a twig of nanotechnology, deals with engineered nanodevices, nanostructures, and nanodelivery system intrusion at the nanoscale for healing disease or refurbishing damaged tissues. The use of nanotechnology to advance nanodelivery systems with more precision and targeting toward the unhealthy or diseased tissues reduces the toxicity of drugs to healthy tissues. The resources being dispensed for nanotechnology across the research world try to designate that nanomedicine may become a common part of healthcare system in few years. Nanomedicine has the potential to enable early detection and prevention, and to essentially improve diagnosis, treatment, and follow-up diseases [3,4].

      Figure 1.1 A blend of nanotechnology and medicine is nanomedicine.

      1.1.2 Tissue Engineering

      Tissue engineering was classified as an associate field of biomaterials and engineering, but having grown in scale and connotation, tissue engineering has become a discipline of its own [5]. Tissue and organ failures are serious and common medical conditions for which treatment options include organ transplantation, surgical repair, artificial prostheses, and drug therapy [6–8]. A researcher in the field of tissue engineering tries to replace the damaged tissues or organs with functional engineered substitutes in body. Stem cells have added a new drive to tissue engineering. They have the ability to self-renew and commit to specific cell lineages in response to appropriate stimuli, providing excellent regenerative potential that will most likely lead to functionality of the engineered tissue [9]. Present biology and pathology reveal that many diseases originate from malfunctioned cells [10]. Differentiation of stem cells into different types of tissues or organs is still a major limiting factor in the area of tissue engineering mainly due to the complexity and multicellular structure of the tissues and organs [9,10].

      1.2 Relationship of Nanomedicine and Tissue Engineering

      Tissue engineering and nanomedicine are new branches of technology and blend of both have virtuous impact on the health sector. There is a strong need for drug delivery systems that can deliver biological signals/growth factors from biomaterials and tissue engineering scaffolds. The ability of nanomedicine to deliver a wide variety of protein and nucleic acid drugs to intracellular compartments from tissue engineering and regenerative scaffolds could greatly enhance control of important processes such as inflammation, angiogenesis, and biomineralization [11]. Nanoscale materials are the fundamental building blocks and functional subunits of cells, including subcellular organelles and extracellular matrix (ECM) components [12]. Applications of nanomedicine are not limited to nanoimaging, diagnosis, drug delivery, and tissue engineering. It has broad spectrum of application in healthcare system [12,13]. Nanostructured surfaces are better carved to stimulate biomolecule and cellular responses than surfaces at coarser length scales [14–16]. Nanomedicine is defined as monitoring, repair, construction, and control of human biological systems at the molecular level using engineered nanodevices and nanostructures [17]. Nanotechnology in drug delivery has contributed several nanocarriers that can have inimitable properties in biological system. Smart drug delivery systems (liposomes, dendrimers) that are incorporated within matrices (polymeric scaffolds and hydrogels) for tissue engineering approaches show sustained delivery of drugs from 3D matrices for tissue engineering (Figure 1.2). A tissue engineering approach is to use a scaffold, either in combination with cells and other extrinsic factors to simulate the environment at the site of the injury. There are two approaches for tissue engineering to regenerate or repair the tissue or organ. The first approach is to regenerate tissue/organ using biomolecules with biomaterial scaffold. The second approach is to regenerate tissue/organ using donor cell or own cell with biomaterial scaffold (Figure 1.3). Whatever the approach being used in tissue engineering, the critical issues to optimize any tissue engineering strategy toward producing a functional equivalent tissue are the source of the cells and substrate biomaterial to deliver the cells in particular anatomical sites where a regenerative process is required [18,19]. Both approaches require 3D scaffold or biomaterial to stitch the repaired tissue. Biomaterials play vital role in the tissue engineering and the spatial and temporal structure of scaffold should be in specified manner to heal the tissue or organ rapidly. The design of the scaffold depends on polymers, method of preparation, molecule size, etc., hereby nanomedicine come into the role of scaffold for tissue engineering. For researcher, ECM is the key component for success of tissue repair. The ECM promotes a unique microenvironment that fosters tissue organization. Scaffold mimics ECM and provides all the desired properties of ECM at the site of injury of tissue or organ. With the development of modern nanotechnology, scaffolds possessing nanometer-scaled features are attracting increased attention for their application in tissue engineering. The dawn of nanotechnology has fetched with it an astounding number of potential applications in the field of tissue engineering. The advent of nanomedicine has provided a systematic approach to study and use of material properties in the size range close to the molecular level. Understanding the properties of materials at nanoscale provides opportunities for fine-tuning of certain properties as well as development of novel functionalities for specific application in tissue engineering.

      Figure 1.2 Use of nanocarriers in three-dimensional scaffolds for tissue engineering.

      Figure 1.3 Approaches of tissue engineering.

      1.2.1 Nanomedicine Approaches in Bone Tissue Engineering

      Failure of some biomaterial in bone tissue engineering (BTE) has revealed that incompatibilities existed between osteoblasts (bone-forming cells) and conventional implant materials. Bone is comprised of hierarchically arranged collagen fibrils, hydroxyapatite (HA), and proteoglycans [20]. These structural components of bone exist from the macroscopic level (centimeter range), all the way down to the molecular level (nanometer range). Polymers (macromolecules) are the primary materials for scaffolds in various tissue engineering applications, including bone and other mineralized tissues. These polymers as scaffold produce poor integration with the existing bone or tissue structure. As we know that nanoscale materials exhibit different properties when compared to bulk materials. Nanostructured biomaterials are designed to mimic natural bone, thereby solving the problem of conventional implants. Nanomaterial constituent components in the range of 1–100 nm have exhibited enhanced cytocompatibility, mechanical, and electrical properties compared with respective conventional micronscale materials [20,21]. One type of novel nanomaterial, helical rosette nanotubes (HRNs), is novel organic nanotubes that mimic the natural nanostructure of collagen and other components in bone. HRNs are newly developed materials evolved from the self-assembly process of DNA base pair building blocks in body solutions. They are soft nanotubes with helical architecture that mimics natural collagen [21]. HRNs of a guanine–cytosine building block possess key elements for their sequential self-assembly toward the formation of stable nanotubes. HRNs have unique chemical and physical properties that make them particularly attractive for drug delivery and tissue engineering applications. HRN hydrogels are used as novel tissue engineering injectable scaffold materials for orthopedic applications [22]. They are used for drug delivery due to their biocompatibility, low cytotoxicity, and their ability to engender a favorable, biologically inspired environment for cell adhesion and growth [23,24]. They have potential to serve as a biomimetic template for HA deposition [21]. They can be modified chemically with various peptides to alter them for specific tissue engineering applications and physically, by drug entrapment within their core and structurally, by synthetically altering their dimensions (length, diameter) to accommodate a broad range of therapeutic modalities [23].

      Another nanostructured biomaterial, nanocoated HA, has shown great improvement in orthopedic applications by coating nanometer-sized (instead of micron) HA crystals on titanium matching the crystal size of HA in bone. Nanophase HA has excellent cytocompatibility properties with osteoblasts [21,24]. The uses of nanoporous TiO2 surface-modified implants, in a human dental clinical study, showed that TiO2 thin film increased adherence in early healing of the human oral mucosa and reduced marginal bone resorption [20,25]. Nanostructured implant surfaces are also known to enhance osteoblast activity [20]. Nanocomposites based scaffolds (e.g., nano-HA/collagen) are very popular in hard-tissue engineering, particularly for the reconstruction of bone tissue [26]. The improvement of the biological activity and performance of bone substitute materials and scaffolds is one of the main concerns in bone regeneration [27]. Bone tissue requires the action of growth factors that provide signals at local injury sites allowing progenitors and inflammatory cells to migrate and trigger the healing process [28]. The growth factors or other signal molecules should be released from the scaffold in controlled manner or in required amounts to elicit the response for regeneration of tissue. Nanodrug delivery plays the role in order to maintain the release in controlled manner. Control of tissue concentration and spatial localization of delivery is essential for safety and effectiveness. Drug delivery is able to fulfill the demand for tissue engineering such as control over the spillage of the growth factor to desired concentration to elicit the positive feedback. Drug delivery guides and controls developmental process in tissue and organ-specific differentiation and morphogenesis by controlling the release of drug. Nanoporous drug delivery system such as nanosponges act as promising candidates for controlling the release of molecules or growth factors for tissue engineering.

      1.2.2 Nanomedicine Approaches in Cardiac Tissue Engineering

      Cardiac tissue engineering (CTE) aims to create contractile heart muscle tissue to replace missing (due to congenital heart defect) or dysfunction of parts of the heart (due to myocardial infraction), thus leading to cardiac repair [29]. Main targets in CTE are blood vessel, heart tissue, and heart valves. Most common biomaterial used for CTE is hydrogel, biodegradable polymeric scaffolds, and decellularized tissue. In CTE, the scaffold material which can imitate the structure of the ECM properly is a key factor. The rapid expansion of nanoscaffolds during the past 10 years has led to new perspectives and advances in biomedical research as well as in clinical practice. The microscopic and submicroscopic structure of the scaffold surface has very important influence in adhesion and growth of the myocardial cells [30]. Electrospun nanofibers have been intensively explored as a tool for the architecture control of cardiovascular tissue engineering due to their tunable physicochemical properties [31]. The product requirement of CTE is that, it must be able to withstand high-pressure fluid dynamics turbulence for blood vessel tissue engineering and must be able to operate in a very dynamic and severe environment for tissue engineering heart valves (TEHVs). Tissue engineering cardiac patch can be used to treat acute myocardial infraction.

      Poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and their copolymers poly(lactic acid-co-glycolic acid) (PLGA) are a family of linear aliphatic polyesters which are most frequently used for cardiac patch in CTE but poor conductivity of these materials limits the ability of the patch to contract strongly as a unit [32–34]. Incorporating gold nanowires within alginate scaffolds or PLA scaffolds can bridge the electrically resistant pore walls of alginate and improve electrical communication between adjacent cardiac cells [35]. A nanofibrous electrospun scaffold made of PLGA/gelatin (PLGA/Gel) was used as a biomimetic cardiac patch containing cardiomyocyte [36]. A combination of nanofiber carriers and stem cell therapy for tissue regeneration seems to pose enormous potential for the treatment of cardiac diseases including atherosclerosis and myocardial infarction [31]. 3D inkjet method is also used to develop artificial valves produced by nanomaterials for TEHV.

      1.2.3 Nanomedicine Approaches in Skin Tissue Engineering

      Tissue engineering is an interdisciplinary area of nanomedicine in which biomaterial and medical science understands pathological tissue and the principles used to achieve this understanding are applied to the improving or sustaining of tissue function through the development of biological substitutes [37]. Tissue engineered replacements play an important role in the treatment of skin wounds, but they are also an option for the treatment of several skin disorders. The nanoporous structure of biomaterials provides adequate cell adhesion onto the matrix, and their hydrophilic properties allow transportation of low molecular solutes and nutrients to the cells [38]. In skin tissue regeneration, drug delivery system like hydrogel is most commonly used as scaffold. In addition to biomaterials, some synthetic materials can be used to increase the body’s ability for regeneration and self-healing, by means of seeding cells on it to form neo-skin tissue. Synthetic polymers have some advantages [37,38]. The efficacy of the hydrogel can be enhanced by incorporating the nanoparticles containing the proteins or drug molecules, which speed up the skin healing or repairing of the skin tissue. Fibroblasts are the cell type best indicated for wound healing purposes. Poly(L-lactic acid)-co-poly(ε-caprolactone) and gelatin (PLACL-G-P) based nanofibrous scaffolds provided enough space for fibroblast ingrowth and induced the formation of a dermal substitute [38]. Epicel, CellSpray, Myskin, Laserskin, ReCell, Integra, AlloDerm, Hyalomatrix PA, Dermagraft, TransCyte, Hyalograft3D, OrCel, Apligraf, and PolyActive are the skin regeneration market products [39]. Nanoporous microspheres have been comprehensively studied in recent years for their applications in tissue regeneration. Use of nanomedicine in skin transplants for larger wounds has been utilized by nanoporous microspheres carrier as suspension culture and transport vehicle for human keratinocytes, which overcome the problem associated in the trypsinization step to harvest cultured skin grafts from cultured dishes that damages the cells by breaking the anchoring proteins and lowers their uptake ratio after transplantation [38,39]. Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres as both cell culture matrix and transplantation vehicle of skin cells for skin regeneration have been studied [40]. A biodegradable nanoporous microcarrier in the culture of autologous keratinocytes for treatment of full-thickness wounds not only facilitates the cultivation, transportation, and transplantation processes but also enhances the dermal regeneration induced by a dermal scaffold which results in a clinical result that is significantly superior to the one obtained when keratinocytes are transplanted in a single cell suspension [41,42].

      1.2.4 Nanomedicine Approaches in Brain Tissue Engineering

      The ideal materials for neural tissue engineering applications should have excellent cytocompatibility, mechanical, and electrical properties [43]. Nanomaterial scaffolds which are popular for the good mechanical strength and cytocompatibility are used in brain tissue engineering. Electrospinning can easily produce nanostructured synthetic polymer mats with architecture that structurally resembles the ECM of tissue [44]. Nanofibrous poly L-lactic acid (PLLA) or poly(ε-caprolactone) (PCL) scaffolds via electrospinning and phase separation have demonstrated excellent cytocompatibility properties for neural tissue engineering applications [34,45,46]. Carbon nanotubes (CNTs)/fibers have excellent electrical conductivity, strong mechanical properties, and have similar nanoscale dimensions compared to neuritis. They have been used to guide axon regeneration and improve neural activity as biomimetic scaffolds at neural tissue injury sites [40]. Thermally responsive hydrogels composed of modified chitosan and glycerophosphate are suitable 3D scaffolding environment for neural tissue engineering [47].

      1.2.5 Nanomedicine Approaches for Other Tissue Engineering Disciplines

      Use of nanotechnology in surface properties of biomaterials has evoked improved interactions with cells for tissue engineering applications. A nanotech-based regenerative approach has been used in various tissue engineering applications like bladder tissue engineering [48], cancer tissue engineering [49], colorectal tissue engineering [50], and craniofacial tissue engineering [51]. Bioresorbable polymeric scaffolds can be regarded as effective platforms to surgically treat bladder diseases and subsequently guide the formation of novel tissue after implantation [52]. Silicone, polyvinyl sponge, and teflon have been first tested for bladder reconstruction with the help of synthetic materials but fail to have cytocompabitlity and caused complication in cell reconstruction. The more recent synthetic polymers including poly(ethylene glycol) (PEG), PLLA, PLGA, PCL, and polyurethane (PU) are used to pursue the bladder tissue engineering research. Only few success rates have been achieved in bladder tissue engineering [53]. Craniofacial structures such as the mandibular condyle, cranial suture, and subcutaneous adipose tissue have been engineered from mesenchymal stem cells, growth factors, and/or gene therapy approaches. Mesenchymal stem cells, the reservoir of mesenchymal cells in the adult, have been revealed, in tissue engineering, to produce key dental, oral, and craniofacial structures [51]. There has been scarce research in colorectal tissue engineering and cancer tissue engineering owing to difficulty in achieving the goal [54,55].

      1.3 Nanodrug Delivery Systems for Tissue Regeneration

      There is ambiguity over the classification of nanomedicine. Personalized health care, nanotheranostics, rational drug design, and targeted drug delivery are some of the classes of a nanomedicine-based approach to therapy. Based on the literature, classification of nanomedicine is categorized to nanodrug delivery, nanoregeneration medicine, and nanotheranostics (Figure 1.4).

      Figure 1.4 Classification of nanomedicine.

      1.3.1 Nanotheranostics

      Theranostics is a combination of therapy and diagnostics. Utilizing particles at the nanoscale level provides numerous advantages in diagnostics and treatment, leading to nanosensors and nanomedicine, respectively [56]. Nanotheranostics implies to apply and further develop nanomedicine strategies for advanced theranostics, i.e., to apply and further develop the various nanocarriers such as polymer conjugations, gold-based nanomaterial, silica-based nanomaterials, dendrimers, micelles, liposomes, metal and inorganic nanoparticles, CNTs, and nanoparticles of biodegradable polymers for sustained, controlled, and targeted co-delivery of diagnostic and therapeutic agents for better theranostic effects and fewer side effects [57]. The advanced theranostic nanomedicines conjugated with targeting moiety can recognize specific target, bind, and be internalized via specific mechanism like receptor-mediated endocytosis [57,58]. Gold-based nanomaterials have been explored as multifunctional probes. Gold nanomaterials can be adjusted by tuning their morphology; gold nanoparticle (AuNP), nanorod (AuNR), nanoshell, and nanocage exhibit distinctive optical and thermal properties, which can readily upgrade gold nanomaterials to be prospective theranostic agents [59]. PEGylated nanocarriers are used as nanotheranostic agents which show slow immunogenicity and antigenicity as well as increases body residence time and stability [59,60]. PEGylated liposomes are used as nanotheranostic liposomes for cancer diagnosis and treatment [61].

      1.3.2 Nanoregeneration Medicine

      Regenerative medicine is the process of replacing or regenerating human cells, tissues, or organs to restore or establish normal function [62]. Stem cells are considered a vital potential source for repairing damaged human tissues in regeneration medicine. Nanotopography plays important role in behavior and fate of the stem cell as a regeneration medicine [63]. Nanotopographic cues may differ in size and shape in vivo, and are crucial for cell adhesion and may be important for stem cell differentiation into specific lineages [64]. Magnetic nanoparticle-based applications in stem cell research open new frontiers in cell and tissue engineering [65].

      1.3.3 Nanodrug Delivery

      Drug delivery systems are engineered technologies for the targeted delivery and/or controlled release of therapeutic agents [66]. They control the rate at which a drug is released and the location in the body where it is released. Inoculation of nanotechnology in drug delivery leads to nanodrug delivery which has shown potential effect on the tissue engineering application. Nanodrug delivery has contributed nanocarriers that can have peerless properties in text of adhesion, controlling or programing the components, and synergetic properties with molecules in the tissue engineering. Polymeric nanoparticles such as dendrimers, hyperbranched polymers, liposomes, polymeric micells, nanogels, and coreshell polymeric particles have gained great attention in drug delivery application due to their ability to entrap hydrophobic or hydrophilic drugs [67,68]. The major nanocarrier used in tissue engineering includes nanoparticles, liposomes, dendrimers, CNTs, and hydrogels (nanogel) (Figure 1.5).

      Figure 1.5 Various drug delivery systems used in tissue engineering.

      1.3.3.1 Dendrimers

      Dendrimers are highly branched nanoscale materials with a tree-like morphology and are applauded for their captivating position in the nanoworld. The highly branched, multivalent nature of dendrimers makes them ideal candidates for a variety of tissue engineering applications, including cross-linking agents, modulators of surface charge and surface chemistry, and as primary components in scaffolds that mimic natural ECMs [69]. Second-generation polypropyleneimine octaamine dendrimers were used to generate highly cross-linked collagen with mechanical properties that would make it appropriate for use as a corneal tissue engineering scaffold [70]. Cross-linking of collagen using polypropyleneimine octaamine dendrimer produces stable gels. The presence of a large number of excess amine groups in the dendrimers may also be useful for subsequent modification with biologically relevant groups [71]. Dendrimers offer state-of-the-art solutions to address tissue engineering challenges such as the strategy of novel tissue adhesives. Unlike linear polymers, like cyanoacrylate or hyaluronic acid, dendrimers are composed of a specific number of branched repeat units that emanate from a central core [72]. Based on the dendrimers’ central core and repeated units, it can be tailored to specific application needed in tissue engineering. The success of scaffolds is determined by the response it elicits from the surrounding biological environment. This response is governed, to a large extent, by the surface properties of the scaffold. Multiple approaches have been developed to provide micrometer- to nanometer-scale alterations in polymer surface to enable improved protein and cell interactions [73]. Compared to linear polymers, the multiple end groups of dendrimers may potentially offer more control over factors such as cell proliferation rates and biodegradation profiles through systematic variation of generation size, concentration, and end group chemistry [69]. A biodendrimer-based hydrogel adhesive has been used for repairing corneal wounds. On the wound interface, such hydrogels serve as additional seal to aid the sutures in preventing the eye from leaking at high pressures and it acts as a barrier against the potential influx of surface fluid into the wound site [74]. A multivalent and water-soluble triblock copolymer consisting of a PEG core and methacrylated poly(glycerol succinic acid) dendrimer terminal blocks in hydrogel formulation act as photo crosslinkable dendritic macromolecules-based hydrogel scaffold for cartilage repair. The terminal methacrylates allow mild and biocompatible photo crosslinking with a visible light, facilitating in vivo filling of irregularly shaped defects with the dendrimers-based scaffold [75]. Dendrimers are well known for their unique properties such as high permeability, high loading capacity, adhesive properties, low immunogenicity, cytocompatibility, sustained/extended effect, high stability, and are well suited for tissue engineering. By virtue of exclusive properties, dendrimers may address all problems related to scaffold in tissue engineering (Figure

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