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In: Biocompatible Nanomaterials Synthesis, Characterization… ISBN: 978-1-61668-677-2

Editors: S. A. Kumar, S. Thiagarajan and S. –F. Wang. ©2010 Nova Science Publishers, Inc.

Chapter 4

Nanobiomaterial Applications in Tissue Repair and Ulcer Management: A New Role for Nanomedicine

Ajay V Singh,2,5 Rajendra Patil,1 Cristina Lenardi,3,6

Paolo Milani,4,5,6 and W.N.Gade,1*

Department of Biotechnology, University of Pune, Ganesh Khind, Pune-411007, India1

European School of Molecular Medicine (IFOM-IEO Campus), via Adamello 16, 20139 Milan, Italy2

Istituto di Fisiologia Generale e Chimica Biologica, Università di Milano, Via Trentacoste 2, I-20134 Milano3

Dipartimento di Fisica, Universita di Milano,Via Celoria 16, 20133 Milan, Italy4

Centro Interdisciplinare Materiali e Interfacce Nanostrutturati (CIMAINA), Università di Milano, Via Celoria 16, 20133 Milano5

Fondazione Filarete, viale Ortles 22/4, I-20139 Milano, Italy6

Abstract

Current decade of tissue repair and ulcer management is experience stimulating change due to advances in nanobiomaterial design and its impact on clinical applications. Over the past years, research in clinical science has seen a dramatic increase in medicinal materials at nanoscale those significantly contributed to tissue repair. This chapter outlines the new biomaterials at nanoscale those contribute state of art clinical practices in ulcer management and wound healing due to their superior properties over traditional dressing materials. Designing new recipes for nanobiomaterials for tissue engineering practices spanning from micro to nano-dimension provided an edge over traditional wound care materials those mimic tissue in vivo. Clinical science stepped into design of artificial skin and extracellular matrix (ECM) components emulating the innate structures with higher degree of precision. Advances in materials sciences polymer chemistry have yielded an entire class of new nanobiomaterials ranging from dendrimer to novel electrospun polymer with biodegradable chemistries and controlled molecular compositions assisting wound healing adhesives, bandages and controlled of therapeutics in specialized wound care. Moreover, supportive regenerative medicine is transforming into rational, real and successful component of modern clinics providing viable cell therapy of tissue remodeling. Soft nanotechnology involving hydrogel scaffold revolutionized the wound management supplementing physico-biochemical and mechanical considerations of tissue regeneration. Moreover, this chapter also reviews the current challenges and opportunities in specialized nanobiomaterials formulations those are desirable for optimal localized wound care considering their in situ physiological environment.

1. Introduction

Wound care and ulcer management has a major impact on socio economic status of developed countries as these represent an exigent and underestimated health problem. Clinical definition for wound may be described as disruption of normal anatomic structure and function and it arises due to skin rupture or defects based on underlying clinical or physiological condition or due to physical, thermal and chemical damage (1). Considering repair mechanism, wound may be further classified as acute or chronic that eludes further decision and selection of treatment strategy. Acute wounds get healed completely in short duration with minimal scarring while chronic wounds take longer periods with frequent recurrence and leave a scar on wound surface. Acute wounds often occur due to mechanical injuries caused by abrasion of skin with hard surfaces or due to gunshot or knives. Many times, surgical incisions turn out to be traumatic in diabetic patient. Another group of acute wounds arises due to burn and chemical injuries acquired due to thermal radiations and corrosive chemicals. They need immediate and special attention due to associated trauma (2). On the other hand, chronic wounds often heal slowly and sometimes even remain as such for longer duration based on underlying physiological conditions, particularly true for nutritional deficiencies, diabetes, persistent infection and malignancies (3). Vascular compromise, arterio-venous and connective tissue disorders due to underlying pressure; define some of major underlying causes of chronic wounds (4).

Wound and ulcer management are major socio-economic problems associated with developed countries as they represents a foul health system involving waste of manpower and health budget (5). Wound healing share a parallelism with injured tissue under reparative process and follows overlapping and orderly phases of homeostasis, inflammation, granulation and maturation or remodeling of damaged tissue , as shown in (figure 1) (6). Further, a balanced event of synthesis and degradation of extra cellular matrix (ECM) components start remodeling the loss tissue and preserve anatomy of original tissue. A successful wound management needs several clinical attentions and understanding based on patient condition (e.g., diabetic Vs non-diabetic), wound type and healing environment, physico-chemical properties of dressing materials and social settings in terms of nutritional requirement of society (7). The best clinical practices and their expected performances in wound management can be summarized as follows (8)

  1. Physical Examination → to assess general health and risk that may delay the wound healing.

  2. Patient History → to assess daily practices of patient that contribute to pressure increment in deep veins/arteries and pain in limb peripheries.

  3. Nutritional Status → to assess micro/macro nutrients for tissue and ECM reparative process.

  4. Physical Status → to asses reduced or absence of friction during mobility for optimum healing.

  5. In situ environment→ to assess moisture, debridgment, infection control and incontinence.

  6. Clinical grading → to assess class of ulcer in order to introduce adjunctive modalities or surgical intervention, if clinically needed.

  7. Patient counseling → to educate health practitioner, patient and caregiver to understand prevention and treatment modalities. Patient counseling also fulfills psychosocial needs of aged patient to overcome low self esteem and hatred towards the disease (9)

Figure 1. An open wound showing sequential and overlapping stages of healing.

In wound healing, overall approach should be interdisciplinary and holistic i.e. it should not only center to wound but it also heal the emotions with the wound as in elder patient it frequently causes hatred.

2. Clinical Requirements in Designing New Materials for Wound Management

The clinician and scientist should have a deep insight beyond dressing and therapeutics supplement while designing new materials for wound management. Since latest biomedicine practices ride on waves of newest and ultra fast techniques, researchers have more broad options while designing dressing and therapeutic materials to assure maximal benefit in crisis driven intervention (10). Some of dos, don’ts and dooms for designing new materials for tissue repair are given below

  • New materials must support debridement in order to encourage the extravasations of leukocyte and matrix synthesizing enzyme at wound site as foreign material and dead tissue prolong inflammatory phase and attract growth of microbes. Materials designed for wound cleansing must absorb exudates.

  • The most important characteristics of dressing materials is to provide and sustain moisture and temperature optima at wound site. Since epithelial cells and ECM components prefer moist milieu that promotes angiogenesis and epidermal migration, moist environment supports ECM component synthesis by preventing in situ desiccation and cell death. Moreover, moist healing promotes fast epithelization and gives better cosmetic result.

  • Materials with sustained aeration at wound site results in reduced exudation and drying of necrotic tissue that in turn prevents granulation and wound contraction It is noteworthy that abused heavy metal metabolism in diet promotes free radical generation in presence of oxygen (11-12).

  • Materials with absorbing characteristics prove to be very useful in chronic wounds where exudates contain ECM and tissue degrading enzyme by blocking growth factor supply to proliferating cells, thus delay in wound healing. Such materials also help in removal of blood exudates and pus formation.

  • Antimicrobial property and low tissue adherence materials are demanding in new age materials as they prevent bacterial/fungal invasion and avoid friction between wounded tissue and dressing materials.

  • Cost effective and reusable materials are in demand as they provide better chances of infrequent change of dressings though later is prerequisite in chronic wounds.

3. Contribution of Nanomedicine in Wound Healing and Ulcer Management

Nanomedicine is providing explosive development to complement and augment clinical and biomedical practices in wound healing and ulcer management due to its better therapeutic outcome. Atomic level control of nanobiomaterials exhibit quantum characteristics compared to their bulk materials and when combined with biological properties, biomolecules exhibit entire new phenomenon in this magic dimension. This is the main reason that nanomedicine is preferred over traditional biomedical practices in recent years. By National Institute of Health (NIH) definition, nanomedicine describes use of nanotechnology in biology and medicine ranging from biomedical applications to molecular nanotechnology and nanoelectronics in developing biosensors for diagnosis and therapeutics (13). Lately, nanoparticles (NPs) have been variously used in targeted drug delivery to improve bioavailability and systemic circulation of drug and an insight into this is reflected by the fact that annual investment in nanobiomaterials has increased to 3.8 billions US $ (14). In past, targeted drug delivery was one of most sought nightmare of pharmaceutical industry. Dendrimer polymer and lipid based drug delivery system had contributed immensely in this regard. Dimensional benefits of NPs provide an opportunity to adapt in systemic circulation and move through the cell membranes and are concentrated and accumulated inside cytoplasm. Design of biodegradable NPs ca.nanoliposomes, nanospheres, nanocapsule, hollow nanostructures, ceramic NPs, dendrimers and polymeric micelles have their own advantages over traditional drug delivery system. They provide sustained release of drug at target sites and can be maintained for longer period in systemic circulations (15). Most important characteristic that attracted these nanomaterials to ambitious researchers for drug delivery, emerges from their easy and reliable surface modification for tissue/organ specific targeting (16)

3.1 Nanomedicine and Tissue Engineering: Promising Partners

Some of standard biomedical applications of above duo are summarized below and shown in (figure 2).

3.1.1 Orthopedic Implants

If there is one field of biomedical sciences that has benefited maximally due to advance developments in nanobiomaterial sciences, undoubtedly it is surgical implants and prosthesis in orthopedics, cartilage tissue engineering and dentistry. The reason for this emerges from severe competition in designing materials sciences for biomedical applications. Nanomedicine holds the tag of champion for implants because it has been observed that nanophase coating of implant materials promotes and encourages surrounding osteoblasts (bone forming cells) to synthesize more of hydroxy appetite (HA) thus giving rise to new bone at the site of damaged cartilage or bone fracture (17). This probably happens as nano-grained surface promotes adhesion and proliferation of osteoblasts and increases synthesis of collagen and alkaline phosphatase that corroborate in vitro mineralization and subsequent calcium deposition. (18-19). One interesting aspect of nanophase adhesion of osteoblasts is that, competitive cells such as fibroblasts adhesion are greatly reduced. This helps in establishing connection between implants to osteogenic tissue as fibroblast prevents such attempts by forming callus and fibrous encapsulation that leads to implant loosening at prosthesis site (20).

3.1.2 Cartilage Engineering

In sports arena, cartilage injury is one of major problem that attracts scientists to design new materials that supports rapid cartilage healing as chondrocytes are nasty cells and do not under go rapid mitosis to regenerate new cartilage since cartilage region has poor vascular supply (21). Often, surgical procedures complemented with encouraging in vivo cell communications with supply of signaling molecules and growth factors, become choice of treatment plan in chronic shortage of bioactive molecules. Before actual cartilage regeneration may begin, damaged cartilage itself receives so many surgical treatments to overcome its crisis driven situation that it further becomes bad to worse. Researcher suggested to synthesize biomaterials by tissue engineering that closely mimics natural tissue in terms of cartilage anatomy, textures, functionality and ECM of surrounding chondrocyte, will overcome this problem (22). In this regards, instead of synthetic materials, lot more insight have been put for natural materials to understand precise mechanism and modeling of cartilage for biomedical applications (23).

3.1.3 Vascular Biology and Nanomedicine

A recent development in material synthesis has given an edge to synthesize biological structures in vitro under ambient lab conditions. These developments coupled with tissue engineering have put forth enormous capabilities of these materials in vascular biology and regenerative medicine. In biomedicine, vascular biology is one of very advance field that seldom needs technical expertise since this field comprises vast cardiovascular premises surrounded by blood vessel and associated structures. Advances in nanomedicine have given a languishing hope to future promises in this field due to ground level cooperation between various fields of basic sciences comprising engineering, medicine, physics, chemistry and biology (24). An in vitro study had revealed that biocompatible nanosurfaces promote growth and proliferation of vascular cells viz. endothelial and smooth muscle cells that paved the way for future vascular stents applications in designing endothelial monolayer (25).

Figure 2. New opportunities in biomedicine provided by biocompatible nanomaterials using advance material engineering.

3.1.4 Application of Nanomedicine in Neurobiology

Advent and increased sophistication of nanotechnological tools provided us an understanding to develop in vitro neuronal circuits using smart carbon materials that can be used for neuronal prosthesis in vivo. Withthe discovery of conductive carbon nanotubes and nanofibres with the excellent biocompatibility, a new hope in neurobiology has aroused specially in neurodegenerative disorders such as Parkinson (PD), Alzheimer's (AD) and Multiple Sclerosis (MS), where such developments will bring million's dollar smile (26). Major problem with neuronal cells is their poor capability to proliferate and their nasty requirement for growth and interaction with the surrounding cells maintaining their neuronal plasticity (27). Nanofibres-polycarbonate urethanes (PU) composite have provided a novel solution to gliotic scar formation in tissues that was a major challenge in neuronal prosthesis and functionality. This composite also provides positive interaction and cooperation among cells in vitro (28). Lately, researchers have shown that neuronal and bone forming stem cell associated with clinical disorder had shown reversal in terms of neuronal/osteopathic anatomy and functionality when cultured in biocompatible environment of composite carbon nanofibres (29).

4. Nanobiomaterials: New Beginning in Wound Healing and Ulcer Management

As updated convention, biomaterials can be defined as substances composed of biologically derived moieties (other than drugs and food) those can be successfully used for therapeutic or diagnostic purposes irrespective of their applications (30). In recent years, biomaterials research has gained momentum due to their significant contribution in biology and medicine (31). Use of biomaterials in tissue engineering is revolutionary rather than evolutionary due to their capabilities to synthesize artificial connective, epithelial, or neuronal tissues (32). One of major breakthrough supporting nanobiomaterials in medicine is their dimensional versatility that ranges from equiaxed symmetrical gold, Pt, Ti nanoparticles (NPs), quantum dots (QDs) to one dimensional fibrous forms (carbon nanotubes/fibers) that make them a suitable choice for wound dressing materials. This dimensional profitability makes them materials of choice in various implants and prosthetic applications where dimensional stability is most important features. For example nanobiomaterials have been used in Zirconium based Joints (hip, knee, shoulder), Cochlear/dental and breast implants, ear and glaucoma drainage tube, mechanical heart valve and articular graft, intra ocular lens etc (33). Nanoclay and nanohdyroxyapatite are used to fillers and reinforce agents to strengthen the mechanical stability of polymers in various prosthetic processes (34). The smart aspect of nanobiomaterials can be evaluated by their smart application in bioelectronics that they not only can touch, feel or stimulate the biological system but also can transmit the information as sensors, biofuels or circuitry elements for versatile biomedical applications that could be another promising approach in design of “electronic skin” (35). These could be used in wound management with supported antimicrobial agents as filling materials in deep cuts and burn cases where we need to cover large surface areas to protect skin and promote rapid healing. The biggest advantages of nanomaterials are their large surface to volume ratio i.e. they can cover large surface area applied. This characteristic provides a unique opportunity in surface healing process where we need minimal therapeutic to cover large area.

4.1 Challenges in Designing Biomaterials for Wound Healing and Ulcer Management

Challenging aspects that might be considered during design of nanobiomaterials for wound healing must consider required biodegradability, surface properties, mechanical properties, shapability to sculpt finer details. Some of the challenges in the designing nanobiomaterials are discussed with following areas-

  • Progress and challenges mimicking ECM biologically and structurally

  • Detail list of biomaterials used for biomedical applications (e.g. soft nanomaterials, hydrogels, fiber scaffold mimicking ECM, dendrimers and electro spun polymers and their advantages)

  • Corneal wound healing, Bladder wall and vascular biology applications: A special use of biomaterials

  • Details of advantageous factors those give an edge to nanomaterials for use over traditional one e.g. surface modifications to prohibit nonspecific protein adsorption, pinpoint and accurate immobilization of signaling molecules over required surface, biologically inspired nanofibres to mimic natural ECM structures, arduous and vociferous design of 3-D architecture to develop in vitro blood vessels with supported angiogenesis.

  • Unique surface energy of nanomaterials: protein-mediated cell interactions (Figure 3)

Figure 3. Schematic plan showing hyaluronan-GAG-core protein cross linking strategy to design artificial skin-ECM Analogue. Fundamental design includes HA-GAGs back bone that supports nanoscale protein-carbohydrate monomer buildings blocks pegged meticulously to mimic biostructure (n.repeating units).

4.2 Artificial Skin: New Concept for Regenerative Medicine

Designing materials for wound healing and ulcer management had taken one-step forward from traditional materials dissecting the conventional thinking to design dressings and antimicrobial supplement. The concept and realization of initial steps of designing artificial skin had given a great hope to regain price and prejudice of aesthetic value in burn cases where often patients has to loose a lot in terms of social values due to lost skin textures that leave a scar after treatment. Natural skin transplant will be the first choice for clinicians and surgeons to replace scarred skin in burn cases, nonetheless designing artificial skin will enhance the scope of regenerative, and transplant medicine to underscore the conundrum of success of man made organ over natural one.

4.2.1 Fundamentals of Designing Artificial Skin

Skin with integument system makes primary defense barrier against microbes and keeps body surface in tune with the external environment. Histology of skin comprises epidermis composed of stratified squamous epithelium, a dermis having dense connective tissue and fibroblasts with underlying hypodermis with adipose and connective tissue fibers. Among above two, epidermis is home of ECM forming keratinocyte, melanin producing melancholy and epithelial cells. Considering design of fully functional artificial skin, graft materials should adhere with wounded skin and should be porous enough to allow diffusion of gases, water, nutrients, waste and most importantly prevent dehydration of surrounding wounded skin. Graft materials should allow migration and relocation of cell components and should be comparable with natural skin in mechanical and electronic properties. Finally yet importantly, artificial graft must support regeneration of underlying dermal layer that in turn will support the regeneration of epidermal layer. These advances on one hand will prevent microbial invasion to wound site, on the other hand give an opportunity to fast healing (36). Material design for artificial skin graft must fulfill nutrient and growth factor requirement, taking care of immunological aspect to avoid foreign body and prevent rejection of its own. Further, they must have inherent ability to integrate artificial tissue with supporting innate vasculature and must be supplemented with cultured skin cells that makes it truly bioactive and helps in establishing connection with the underlying natural tissue (37). Moreover, we need to put the basics on designing skin with mechanoreceptors, pressure and tactile receptors with impregnated hair follicles and nerve branching. One fascinating work had reveled construction of nanotransistors tagged with large area, flexible pressure sensor matrix that eventually work as electronic skin for futuristic nanorobots aimed to surgical procedures in vitro (38). So for progress made in this area adapted discriminative approaches supplying grafts with cultured epidermal cells in one case, cultured dermal in another case and a supplement of duo in third case. Researcher suggested that grafts with dermal layer after regeneration supports a subsequent auto graft and provide best opportunity in burned tissue regeneration (39).

Basic design of artificial skin must include the vide infra scope of chemical composition that leads to the fundamental success of the story. Studies hypothesizing importance of chemical compositions have given insight that collagen- glycosaminoglycan (GAG) membranes cross linked with glutaraldehyde (as cross linking agents), used as artificial skin, had shown to have capacity to escape fluid loss and infection over longer period of time (Figure 4).

Most important they prevent graft rejection and contraction of wounds that is of primary importance for cosmetic purposes in facial wounds and functional importance in corneal wounds since contraction in corneal wounds produces astigmatism (40). As an evidence, chemically crosslinked glycosaminoglycan (GAG) with hyaluronan (HA) and chondroitin sulfate (CS) as an active ingredients have been shown to perform better wound dressing materials than the traditional one (41). A broad comparison showing beneficial characteristics of nanobiomaterials over traditional one has been shown below in table 1.

Figure 4. Rational design of synthetic ECM with applications as responsive instructive clue to attach and proliferate the cells in vitro mimicking innate ECM. Such design with controlled release of more than one growth factors with superior diffusion rates in spatial microenvironment, exhibit enhanced binding of cells to the ECM substratum.

Table 1. Comparison of traditional materials over nanobiomaterials for dressing purposes and therapeutic purposes.

Characteristics

Traditional Biomaterials

Nanobiomaterials

References

Thermal sensitivity

moderate due to meso-micro scale modification

higher due to nano scale modification

42

Hydrophilicit

less to moderate

more hydrophilic due to surrounding temperature control

43

Cell Attachment& grafting

less due to low protein interaction surface energies

more due to higher surface-volume ratio

44

Biocompatibility& biodegradability

less than nanobiomaterials

more due to biological origin and bio-polymers

45

Fluid retention

less in traditional gauze based dressing materials

more due to hydrogel based dressing

46

Bioadhesive and antimicrobial

require external antimicrobial supplement

impregnated into nanoporous membrane

47

Tissue abrasion

more to moderate

least due to foam based air fluidized

48

Mechanical properties

sufficient but less than new materials

more due to nanopolymer layer

49

4.3 Designing of Biomaterial Mimicking ECM using Nanoscale Tissue Engineering

ECM defines extra cellular part of cell that often provides structural supports to cell and more precisely defines connective tissue. ECM regulates cell's dynamic behavior in terms of intercellular communication and deporting a number of growth factors those helps in cell signaling and cell anchorage in various biological phenomenon (50). It becomes an important issue to consider ECM morphology and function when considering design of nanobiomaterials for wound healing and reparative tissue management as formation of ECM is the fundamental process in morphogenesis, wound healing, growth and fibrosis. Deep understanding ECM components such as proteoglycan and non-proteoglycan (GAGs) that form a matrix by interlocking with the fibrous proteins, will help to assemble biological moieties to form artificial ECM membrane for wound healing and burned skin. ECM contains cell-binding domains those interact with cell receptors and transmit cellular signals to cell-cell/cell-ECM adhesion and binding. ECM mediated cell signaling also helps in sequestering various bioactive molecules such as fibrous proteins, GAGs, growth factors and cytokines which is important steps in tissue remodeling at wound sites. Realization of biomaterials mimicking ECM for wound healing must have some fundamentals similarity as shown in figure. 4 and mentioned below.

4.3.1 In vitro ECM synthetic analogue

Artificial design must sketch structural and functional relationship between ECM and biomaterials that can sustain and respond pharmacological action at living tissue and engineered interface. Some studies had shown nanofibre scaffold mimicking ECM designed by tissue engineering (51)

4.3.2 Dynamic Interaction among Cell Components

Nanobiomaterials must exhibit a dynamic microenvironment at wound site to facilitate cross talk among soluble (growth factors, cytokines, morphogens) and insoluble components (cells, ECM components) under ambient chemical environment (pH, O2) to establish a vital connection between the living tissue and nonliving biomaterials.

4.3.3 Tissue Regeneration

Most sought requirement of designing ECM replica should support tissue regeneration at wounded tissue site. This could be achieved by meticulous surface modification of proteins and cell binding domains and incorporation of such ligands (RGD, IKVAV) in molecular design. The scaffold must provide a guided mechanical platform for new skin growth (52).

4.3.4 Active Cellular/Tissue Responses

Biomaterials design so for give nonspecific responses towards biological system due to inappropriate design of cellular components. This is major challenge to today’s material research to pinpoint the target specific receptor to respond cellular functions viz. adhesion, proliferation and differentiation in artificial design of molecular components. This needs controlled incorporation of cell binding and enzymatic sequences sites in bioactive design.

5. Special Application of Soft Nanomaterials

5.1 Corneal Wound Healing

Corneal wounds repair is of paramount importance as cornea is site of refraction and focusing light in order to make correct vision. Non-vascular nature and patterned collagen fibrils provide characteristics transparency to cornea that makes it special tissue for normal vision. Corneal wounds are caused due to a number of reasons including corneal ulcer, ocular surgery (intraocular implantations, incisions for cataract surgery, in situ keratomileusis and transplants) and trauma caused by lacerations or perforations. Currently, nylon sutures are choice of surgical procedures but they achieved cold reception from clinicians due to some undesired properties. Nylon sutures often cause wound constrictions and asymmetrical healing that often leads to astigmatism. Moreover, suture and incision during ocular surgery inflicts additional trauma to corneal tissue and thus inflammations and vascularization ending into corneal scar that contribute significantly to astigmatism. More often, sutures need special attention and technical skills by trained ophthalmologists in order to avoid postoperative loosening and corneal trauma during in and out of suture removal. (53). Therefore, technological skills to design new surgical materials and tools constitute competitive race in this field in order to restore natural vision and patient care in ophthalmic and corneal wounds healing. Designing new recipes must consider technical achievements mentioned above. Considering above design requirements, we need a polymer adhesive that can seal corneal wound rapidly and accurately restoring correct intra ocular pressure ( > 80 mmHg) and must comprise sufficient viscosity allowing clinician for precise placement and workability (viscosity < 100 cP). Moreover, polymer adhesive must restore structural integrity of patterned collagen fibrils to provide native corneal transparency to focus the lights accurately and most important elastic modulus of polymer adhesive must be greater than corneal tissue to negate any possibility of astigmatism. Solute diffusion properties, biocompatibility, microbial barrier and biosorption of wound exudate are additional designing essentials where beauty meets utility for corneal wound care (54). Fundamentals of corneal wound management require repairing lacerations and clear sealing of incisions with securing corneal transplants. Closings of LASIK flaps are other ophthalmic indicators where nanoadhesives may prove to be landmark success. Next age materials such as polymeric dendrimer provide unique solutions to special wound care such as in corneal and ophthalmic injuries. “Biodendrimers” made up of polyethylene glycol (PEG), succinic acid (SA) and polylactic acid (PLA) are unique biocompatible and degradable polymeric dendrimers that shows controlled hydrophilicity and cell attachment/detachment properties (55).

Further, capability of peptide-ligation based soft cross-linking avoids complex photochemistry and procedural risks that makes this more amenable for clinical procedures. Peptide cross-linking provides additional support to physico-mechanical properties (e.g. modulus and plasticity) and fit for clinical response in situ (56). Peptide lock and cross links in hydrogel and adhesive used for corneal wound care further give possibility to peptidases based easy cleavage when it comes to integration of nano-domain protein or monomer in multigenerational biodendrimer synthesis

Figure 5 (a). Dendrimer with internal cavity, core and branching units with unique interior and surface chemistry to couple the therapeutic pay-load (colored dots show simultaneous loading of different drug molecule delivery at wound site). (b) Cartoon showing sequential addition of generations in those has advantages over controlling globular/innear/symmetrical faces of dendrimer to design 3-D architecture. Inset showing interaction of ligand-receptor complex at dendrimer surface (yellow line shows peptide spacer linked to ligands).

5.2 Nanobiomaterials for Synthetic Bladder Wall Substitute

A large number of populations suffer from cancer and disorders related to bladder. In absence of suitable surgical treatment and chemotherapeutic panic, removal of entire bladder wall is considered best strategy to prevent the recurrence of bladder cancer and disorders. Considering essentials of designing new materials, mimicking topographic features of bladder wall with stretchability, mechanical properties and optimal knowledge of cellular and molecular events in vivo, are the main requisite. Surface features of bladder gives an understanding of designing biological nanostructures, such as nano-dimension extra cellular matrix constituent proteins that should be precisely incorporated and tagged with the biological moieties to give maximal cell response. Researchers have designed nano-dimensional poly (latide-co-glycolide) acid (PLGA) and polyurethane (PU) based artificial structures mimicking bladder topography in 50-100 nm range those exhibit excellent in vitro cytocompatibility and enhanced bladder smooth muscle cell adhesion and proliferation (57). Designed materials show parallelism with in vivo functionality of natural bladder wall that opens new avenues for nanobiomaterials for designing tissue engineered artificial structures (58).

5.3 Nanobiomaterials in Artificial Blood Vessel Replacement: A Special Case of Intravascular Wound Healing

Apart from surface wound, deep vascular tissues often meet intra vascular tissue damage due to ischemia and perfusion such as in myocardial and endothelial injuries which need immediate clinical attention, being part of vital organ (59). More often cardiac procedures are supplement with bypass surgery of affected blood vessels with autologus arteries or veins of less than 6 mm diameter, in order to reduce procedural and invasive risk of heterologus grafts rejection (60). Many myocardial infarction patients need an alternative to innate blood vessels in coronary artery bypass graft surgery (CABG) as a replacement to their diseased or sclerosed blood vessels (61). In this regard, the design strategy involving core technology must meet a number of cell construct in vitro that can precisely mimic the vessel architecture and land marks in vivo with respect to biochemical and biomechanical aspect. New age biomaterials and micro to nanoscale technologies provide artistic liberty to meet the precision in this regard by meticulously mounting biochemical building blocks. For example, artificial endothelial layer production needs cross linking of collagen fibers, integrated with growth factors needed for cell communications between different vessel wall layers (62). Lately, in vitro studies shown that radial stresses induced by cyclic stimulations give better mechanical strength and histological organizations in which cells get arranged circumferentially through out the wall thickness like natural blood vessel wall. This mechanical stimulation plays a key role in precise netting and increasing collagen content in artificial structure compared to unstrained controls. (63). Evidence to mechanical conditioning that stimulates cell mediated construct remodeling is demonstrated by over expression of matrix metalloproteinases (MMPs). These are expressed in relation with the production of ECM structural proteins (elastin and collagen) and reinforce the remodeled tissue (64). This is further supported by increased level of collagen and elastin mRNA content in mechanically stimulated and cyclically strained cells in vitro (65).

Another most important factor that paves success of artificial design of blood vessels is cell technologies enabling pinpoint cell manipulation and their controlled functionality. These features can be further regulated by creating extracellular environment of embryonic cells (ECs) utilized for making synthetic grafts by encapsulating them in reconstituted collagen matrix, providing functional vaso-activity in biological scaffold (66). By inducing endothelialization in synthetic graft, it is possible to design an artificial blood vessel. This construct should contain an outer adventitia made of fibroblast and collagen, a middle layer (media) made of mesenchymal stroma cells (MSCs) and ECs based internal monolayer (intima), when molded in tubular fashion.

6. Detail insight into Nanomaterials used for Wound Healing and Tissue Repair Process

6.1 Dendrimer: Fancy Fractals for Nanomedicine

Dendrimers are globular species with defined symmetrical features including core, branching sites, and terminal groups (67). Physical and chemical properties of dendrimers can be precisely controlled by chemical manipulations. Dendrimers are highly branched structure that holds 3-D globular structure; in which each branch is termed as dendron mimicking neuronal branching. Each layer of branching is termed as generation (G) and as we increase umber of generation (G0-Gn); their globular shape increases like in biological system protein subunits and cellular components unite to form cellular and extra cellular matrices as shown in (figure 5, a-b) (68).

What makes dendrimer so special for biological applications is their artistic 3-D molecular architecture that can be designed to desired chemical and biological reactivity. Moreover, their interfacial cross talk with environment makes them endear to clinicians and researcher for biomedical applications that is controlled by pecking functional chemical moieties at needed topographic surfaces (69). The gold standard of dendrimer application can be estimated by their applications ranging from drug/gene delivery, vaccine carrier, imaging agents to bioscaffold for tissue repair (70).

6.1.1 Exclusive Factors Favoring Dendrimer as a Good Candidate for Tissue Repair Process

The governing features those make dendrimer materials of choice for wound healing and tissue repair includes easiness to modify their surface features for controlling hydrophilicity and cell attachment/detachment those are central issues for choosing materials for tissue repair. Another feature that had given an outstanding praise and price, is architecture based ligand binding sites that is utilized as therapeutic metal binding sites on surface and interior of this macromolecule.(71). This could be a sterling opportunity for supplying antimicrobial metal therapeutics to wound sites in order to prevent infection and rapid healing. Silver and its metal complexes are proved antimicrobial agents in burn cases to prevent bacterial infections that are major cause of morbidity in thermal injuries (72). Silver sulfadiazine (AgSD) is gold standard therapeutic in burn cases in last few decades that slowly released in tissue microenvironment and subsequent leaching to wound site leads to silver action on microbes (73). AgSD is posed with slow release at wound, more often due to formation of Silver chloride reacting with tissue fluids in situ that inspired researcher to think about any better alternatives (74). Silver-poly (amidoamine) (PAMAM) dendrimers provides an unique solutions. Dendrimer core-shell structure and its globular shape gives a novel platform to impregnate silver metal to form antimicrobial complex which prevents interruption from tissue fluids micro-environment interference and pays its therapeutic load to wound site against Staphylococcusaureus, Pseudomonas aeruginosa, and Escherichia coli (75). Another shape utility of biodendrimer that can be associated for its beneficial use for tissue repair process is silver nylon dressing substitute that can make it more cytocompatible and tissue friendly. The dendrimer branching with impregnated antimicrobial agents may give an additional benefit to cover large area per micro square allowing slow release of drug and tethering the ECM surface to bind together (76).

Another important feature that gives dendrimers an edge for tissue repair process is that vast choice of synthesis recipes with capability to introduce and control desired physical (flow and hydrophilicity) and mechanical (plasticity) properties with additional biological growth factors precisely resembling with the wound to be repaired. Matching such features gives an opportunity to prevent wound contraction and aesthetic losses since introducing homogeneous ECM features supports cellular interaction and symmetrical tissue remodeling at wound site (77). Contrary to traditional dressing polymers comprise mixed molecular weight (m.wt.) which is differential distribution of m.wt. around wound vicinity, dendrimer having single molecular weight composition giving uniform and smooth healing devoid of any scar (78)

Moreover, control on bio-mechanical and chemical properties design will promote to manufacture biodendrimers for inter penetration and hydrogen bonding interaction with the proteins, cross-link with ECM, and fix exposed/open tissue in place that we can get good adhesion with tissue preparative materials (79). These also can be used as sealant to relive suture stresses at epithelial and stromal tissue interface.

6.2 Nano-Hydrogel in Tissue Repair: Soft Nanochemistry in New Role

Hydrogels are hydrophilic, insoluble and swallowable materials; made up of natural (alginates/chitosan/agarose/chitosan/fibrin) or synthetic {(Poly (acrylic acid) and its derivatives; poly (ethylene oxide) and its copolymers and polyvinylpyrrolidine, polypeptides and their derivatives} polymers (80). Hydrogel derived from biopolymers and designed as bioscaffold precisely mimic ECM in its chemical compositions comprising numerous amino acids, fibrous proteins, growth factors and sugar. Designed hydrogels also contribute to ECM functions by bringing cell junction together, recruiting growth factors for cell communications, allowing extracellular metabolite/nutrient transport, and most importantantly controlling cellular architecture in vitro (81). In last few decades, realization of artificial prosthetic organs ranging from dentin, cartilage, ligament, tendon, bone to soft vascular prosthetic implants (arteries, bladder, skin) have been made possible due to generous hydrogel based scaffolds (82).

Figure 6. Image showing immunostained cells growing (left panel) fine network of hydrogel mesh (right panel) housing granulated collagen, growth, network of keratinocyte and chondroitin 6-sulphate as viable skin for wound repair.

Lately, uses of hydrogel for wound healing and tissue repairs process have gain applause in medicine based on capability to design and control their physical properties as per tissue repair requirement and support for tissue remodeling (83). Hydrogels have been devised for occlusive dressing, cartilage tissue repair, injectable cellular scaffold, axonal regeneration in spinal cord injury and tissue sealant in neurosurgery (84-88). Yet there are many open prospects those can serve for more advance use of hydrogel as novel nanomaterials for tissue repair. One novel strategy could be design of hydrogel based bioscaffold comprising fibronectin functional domains (FNfds) and hyaluronan (HA) for tissue repair. Since FNfds hydrogel matrix is a tremendous medium for promoting wound healing by binding with the platelet derived growth factors (PDGFs), it assists with the fibroblast migration in situ that is a crucial step for tissue induction for remodeling of injured tissue (89). As mentioned above, hydrogel matrices are available in a wide range of designs from nanoporous, fibrous to fine network of embedded proteins. 3-D hydrogel matrices give a unique opportunity for designing artificial ECM pegged with growth factors and therapeutics required for rapid healing as shown above in (figure 6).

Such designs, mimicking porous and fibrous ECM will support cell growth and migration by trapping fibroblast and other inflammatory cells required for tissue remodeling (90). More ambitious; 3-D hydrogel architecture housed with the cultured fibroblast with growth factors, acts as smart natural skin to establish aesthetic remodeling of lost skin in burn cases and massive injuries with severe tissue loss (91).

6.3 Electrospun Polymers Scaffold: Tissue Repair at the Rate of Spinning Chemistry

Biomaterial designers have given a new horizon to biomedicine by developing procedure to control nanostructure by introducing biocompatibility, mechanical stiffness, stability and biodegradability. Electrospinning, electrostatic and gas blowing technologies had given an edge to design nanowoven fibrous materials from organic/inorganic to biological polymers. Simultaneously we have control over porosity and diameter, mesh size, texture and pattern giving larger surface area and high surface to volume ratio (S/V) for biomedical and industrial applications (92). Nanofibrous materials have secured their application from medicine, cosmetics, tissue scaffold for implants to industrial purposes depending upon nanofiber shape, alignment and cross section that are exclusive features in selecting the fiber materials for a particular application (93). One of biggest advantage that we can count over use of electro spun scaffolds for wound healing and tissue repair process over native polymers is their physical resemblance with ECM in native tissue, which makes them a promising candidate for regenerative medicine. Electrospun ECM substratum camouflage gives an opportunity to assess cellular function in vitro and applications where such scaffolds are used as cell delivery vehicles and viable cell grafts. Compare to traditional polymer engineering techniques, electrospun polymer nanofibers involve controlling a vast array of parameters. This characteristic is tremendously important for their application in postoperative surgeries and stimulating tissue regenerations by promoting adhesion, proliferation, and differentiation cellular flora at the wound site (94). Further, electrospun materials fall in both i.e. natural and synthetic polymer categories. Clinicians have free option to choose best for our tissue repair mechanism that can either support physical (strength/durability) or biological (cell attachment and proliferations) functionalities, or both and indeed researchers had shown is past such subtle advantage while combining the two (95). Thus, above findings reveal the potential of electrospun polymer applications one step ahead to develop the “artificial skin” and “smart ECM Grafts” for tissue repair in severe clinical crisis such as heavy burn and injuries involving massive muscular damage.

Recently polymer colloids have attracted much glare in biomedical applications due to their superior properties of design and feasibility to introduce branching and biodegradability (96). Polymer colloids are 100-400 nm diameters with great architectural diversity. Their ability to easy encapsulation, modify hydrophilicity/hydrophobicity and sustained release at application site, makes them good candidate for their surgical use in arteries and connective tissue. Moreover, new categories of polymer colloids can be designed based on requisite as per biomedical applications. Polymer chemistry has given and opportunity to design resorbable colloids those could be used as promising wound dressing materials (97). In addition, resorbable colloids offer great commercial viability for clinical applications such as postoperative anti-adhesion membranes in trauma. Another benefit these resorbable colloids offer is that anti-adhesion biofilms that on one hand offers excellent biosorption barrier to prevent postoperative complications; on the other hand, it undergoes self-degradation when tissue remodeling is completed at augmented wound site.

Parts from aforementioned applications, electrospun polymer scaffold have been used in many clinical emergencies as artificial implants for tissue repair. Electropsun nanofibres have been developed into different tissue scaffold combining cultured cells with natural and biocompatible materials depending upon clinical requirement as given in table 2.

Table 2. represents electrospun nanofibres conjugated (using coupling chemistry) with the mammalian cells, natural and synthetic biocompatible materials for various tissue management clinical practices.

Clinical Conditions

Biomaterials

References

Nerve Implants

Neuronal Stem Cell+Poly(L-lactic acid)

98

Vascular Grafts

Myofibroblasts, Arterial Smooth Muscle Cell

Human coronary artery endothelial cells, PLA, Collagen type I&II, Elastin

99-100

Bone Implant

Osteoblast, Mesenchymal stem cells+Silk/polyethylene oxide/hydroxyapatite / bone morphogenetic protein

101

Cardiac implants

Cradiomyocytes and myoblasts+Polyaniline and gelatin, Polylactide

102-103

Human ligament Implants

ligament fibroblast+Polyurethane

104

Cartilage Implants

Chondrocytes+Collagen Type II

105

Skin Implants

Human Fibroblast and Keratinocytes+ Collagen type I coated with collagen type I and laminin, Poly(lactide-co-glycolide)

106-107

Breast Implants

Human Fibroblast and Keratinocytes+ Collagen type I coated with collagen type I and laminin, Poly(lactide-co-glycolide)

108

7. Concluding Remarks and Future Directions

Development in nanomedicine had offered many opportunities to improve wound healing and tissue repair process due to progress in biomimetic approach to design bioactive nanomaterials with much closer to natural tissue with respect to structure and function. Research in this area have responded to long arguments in scientific community by putting forth rational advances to develop artificial skin and ECM analogues which can be an innovative supplant for future clinical emergencies needing commendable tissue repair back up. Recent advances in nanotechnology such as electrospinning have given liberty that is more artistic to researcher while designing the materials of clinical as well as aesthetic superiority.

Present chapter outlined the principal clinical requirement for wound healing and their subsequent challenges and applauding measures provided by recent developments in nanomedicine and materials science. Perspective arduous biomedical challenges and their possible solutions in designing artificial skin and ECM have been reported provided with ambitious progress in materials sciences. We also reported the use of nanobiomaterials in special clinical practices such as corneal wound, bladder wall and vascular biology applications where we need to put maximum precautions while developing new materials. In addition, details regarding state of the art nanobiomaterials such as dendrimer and polymers (electrospun and hydrogel) those have served in tissue repair process are mentioned. Artificial implants used as grafts in various injuries, designed by electro spinning techniques have been referred in this review. Moreover, comprehensive details of future promises of nanobiomaterials in service of tissue repair have been presented with this review.

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*Correspondence: Prof.W.N.Gade

Department of Biotechnology, University of Pune, Ganesh Khind, Pune, 411007, Maharashtra, India. Ph: +91 20 25694952 Fax: +91 20 25691821, e-mail : wngade@, Ph: +91 20 25694952 Fax: +91 20 25691821



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    ... applicationsin physics to more general applicationsin physics, chemistry, materials science and ... Siu Approved Advanced NanoBiomaterials Imaging Facility Project ... and its ability to repair, cancer and ... function in intact brain and muscle tissues. The ...
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    ... and Cancer Treatment; Embriyonic Stem Cells andTissueRepair; Adult Stem Cells andTissueRepair; Stem Cells and ... and spinning systems; Nanotechnology applicationsin fibres and yarns production: nanofibres, electrospinning and nanoadditives used in ...

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