INTRODUCTION:

Biomaterial was first defined by Professor Williams as ‘‘materials intended to interface with biological systems to evaluate, treat, augment or replace any tissue, organ, or function of the body’’.¹ The use of surgical suture has been observed in 3000 BC in ancient Egypt while the first dental implant was found in Europe around 900 AD. The study on biomaterials is usually known as biomaterial science or biomaterial engineering which includes aspects of chemistry, biology, medicine, tissue engineering and materials science. From the start of its journey it has experienced sound and strong development with many companies and Governments by means of a lot of funds in developing new products.

Biomaterials are produced either from nature or prepared in the laboratory by several chemical approaches using metals and their alloys, polymers, ceramics, composite materials, etc. These materials are used to medical purposes involving the total or a section of the living systems, thereby performing, enhancing, or replacing a natural function of human physiology. These materials are highly sophisticated and sensitive during the course of its application, use and interactive functioning such as it is used for a heart valve, as hydroxy-apatite coated hip implants, etc. These materials are regularly used in our every day’s life such as in dental applications, surgery and drug delivery. Such applications lead to a patient to be relieved from a prolonged discharge of a particular drug over an extended period of time. It may also be an auto graft, allograft or xenograft employed as a transplant material.

These advance materials are expected to augment the regeneration of natural tissues in near future. This will help in promoting the restoration of structural, functional, metabolic, biochemical and bio-physical performance.²The development and implementation of novel, cost-effective and biocompatible materials is highly essential to improve the physiological conditions for implants required for people.³ In this context, it is important to mention that the processes employed for the development of biomaterials should be affordable, fast, and easy to perform. For quite a long time various techniques have been used by several researchers for the generation of new bioactive, biocompatible materials with osteoconductivity, and osteoinductivity,^4-13e.g. bioglass 45S5 is capable to bind with bone by forming a hydroxyapatite surface layer.¹⁴

Recently, this category of molecules has been used widely as drug delivery systems. In this case, polymers and biodegradable polymers act as potential agents as these compounds target drug discharge.¹⁵It is to note that, an ideal drug deliverer should be capable of transporting a biologically active molecule at a certain rate and for a certain duration to the desired target, so as to maintain the drug level in the body at optimal therapeutic concentrations with least fluctuation.^16,17The use of drug delivery systems can overcome the difficulties associated to conventional drug administration routes, such as oral and intravenous administration.

Historical background:

The use of non-biological materials was observed in a human body found about 9000 near years old near Kennewick, Washington, USA. According to the report of different archeologists, a tall, healthy, active person was walking through region of southern Washington with a spear point fixed in his hip. Such kind of implant was performed by foreign materials and the spear point was slightly similar like modern biomaterial but it was a “tolerated” foreign material implant.

Around 600 A.D. the Mayan people designed nacre teeth from sea shells which is as like as our recent bone integration. A 200 A.D. old body was also found in Europe with dental implant by iron. Galen of Pergamon (circa 130–200 A.D.) depicted ligatures of gold wire. Metallic sutures were mentioned in early Greek literature. In 1816 Professor Philip Physick, University of Pennsylvania, studied various reactions using lead wire sutures. J. Marion Sims, of Alabama performed many successful operations using a jeweler fabricate sutures of silver wire in 1849.

Biomaterials were extensively used throughout medicine, dentistry and biotechnology at the beginning of the 21st century. Fifty years back, one could not imagine about the use and application of biomaterial which we are applying nowadays. At that time excepting the producers of external prosthetics such as limbs, fracture fixation devices, glass eyes, and dental devices there were no other medical device producers, no formalized controlling endorsement processes, no considerable biocompatibility and certainly no academic courses on biomaterials. So far, crude biomaterials were employed generally with poor to mixed outcomes, throughout the history. Considering the entire introduction and development, the history of biomaterials can be classified into four periods such as prehistory, the period of the surgeon hero, designed biomaterials/engineered devices and the modern period leading into a new millennium.

Important dates in biomaterials history:

1628: William Harvey, famous physician, promoted a relatively modern concept on heart functioning as “The heart’s one role is the transmission of the blood and its propulsion by means of the arteries to the extremities everywhere.”

1812: The renowned physiologist Le Gallo introduced the idea that biological organs could be kept alive by circulating blood through them.

1829: Henry S. Levert, an American physician, started to evaluate the efficacy as well as safety of different metallic sutures on dogs.

1870: Dr. Joseph Lester introduced aseptic surgical techniques which were free from contamination by harmful bacteria, viruses or other microorganisms.

1886: Dr. H. Hansmann used metal plates for internal fixation.

1931: Dr. Smith Peterson developed a metal cup for partial hip implants.

1939 – 1945: During World War II many materials and orthopedic surgical techniques were introduced involving metals mostly because at that time there was a very few plastics.

1947: The first paper on polyethylene was published as a synthetic implant material.

1949: A paper was published about plastics “sweating out” additives such as cellophane, Lucite and nylon, resulting in a strong biological reaction.

Advance biomaterials and applications:

Studies involving various aspects and features on biomaterials have been increased significantly and steadily over the previous fifty years. It encompasses aspects of medicine, biology, chemistry, and material science. These materials have several applications, such as joint replacements, bone plates, bone cement, artificial ligaments and tendons, dental implants for tooth fixation, blood vessel prostheses, heart valves, artificial tissue, contact lenses, and breast implants.¹⁶the investigation on useful biomaterials is truly becoming more diverse, bringing together knowledge from a variety of disciplines.

Smart Polymer:

High-performance smart polymers undergo remarkable changes in their property owing to a minor change in the environment. These materials respond to physicochemical factors such as temperature, pH, electric or magnetic field, intensity of light, biological molecules, etc., which brings macroscopic responses in the material, such as swelling/collapse or solution-to-gel transitions, depending upon the physical state of the chains.¹⁸Moreover, most polymers can easily be functionalized by pre-polymerization¹⁹or post-polymerization²⁰methods including functional molecules to the structure as like as biological receptors.²¹ Thus researchers of polymer material have an extensive range of features in terms of polymer chemical structures, polymer architectures and polymer modifications to progress a lot of applications for these smart materials.²⁶

The smart polymers become extraordinarily effective due to its nonlinear response. A significant modification in structure and properties may be induced by a minor stimulus. Once upon a time a change in its functioning is established it could not be changed further as the final state is too stable. The basic reason of effectiveness of smart polymers is their inbuilt nature of polymers. The different monomer units which, alone, would be weak are changed through the change of incentive by the response of strength of each molecule. Such kind of weak responses are the reason of hundred or thousand times significant force in driving biological processes.

The circumstances of near transition, monophasic to biphasic state changes occur for linear and solubilized smart molecules, giving rise to reversible sol–gel hydrogels. At transition situation polymer molecules undergo rearrangement through chain reorganization from cross-linked networks and hydrophilicity as a function of a stimulus thereby. This behavior helps the smart polymer for different applications such as minimally enveloping injectable systems,^22-24pulsatile drug delivery systems^25,26or new substrates for cell culture or tissue engineering.²⁷

Applicationsin tissue engineering:

Nowadays tissue engineering is a significant auspicious biomedical technique which helps in regeneration and restoration of defected and injured tissues based on the natural healing abilities of patients.²⁸ The novel approach in tissue engineering is cell sheet technology excluding the use of biodegradable scaffolds.²⁹ The smart polymer is the origin of cell sheet technology containing temperature-responsive culture dish which allows reversible cell adhesion and detachment from the dish surface by controllable hydrophobicity of the surface.²⁹ So, it has been introduced for scaffold-free tissue renovation with clinical applications in reformative medicine.^29-31 Okano and his coworkers proposed such temperature-responsive cell culture polystyrene substrates which were prepared by the grafting of poly (N-isopropylacrylamide) onto these surfaces. This permitted the culture of confluent cell monolayers at 37°C and their retrieval as single cell sheets. According to the model of smart surfaces in well-defined geometries ordered layering of cell sheets permits the manufacture of complex and organized 3D tissues.^32-36 Smart biomineralization, heart valve and vascular graft tissue engineering, delivery systems of therapeutic agents, hydrogels as injectable implants, etc., are also the other applications related to tissue engineering.

Application in fabrication of new medical devices and others:

Smart polymers have played an imperative role for the manufacture of new medical devices for cancer analysis and treatment. In this area, magnetic nanoparticles have been used in developing hyperthermia treatments, magnetic separation, immunoassay, cellular labeling, magnetic resonance imaging diagnosis, etc.³⁷ Biosensors based on smart polymer is an active bio-material in clinical and forensic analysis, because modifications of the concentration of certain analyses such as glucose in diabetes³⁸ or in physical variables such as temperature or pH occur in several diseases. The pH-sensitive polymers are polyelectrolytes, having weak acidic or basic functionalities in their structure that either can accept or release protons in response to change in environmental pH. This kind of biomaterials has extensive applications in analyzing numerous diseases such as the quantification of partial pressure of CO₂ in the stomach for the analysis of gastrointestinal ischemia.³⁹Biosensors and actuators are combined in medical devices, for example, a glucose-sensing and insulin delivery medical device⁴⁰ or cochlear implant.⁴¹ Microfluidics-based medical utility or lab on a chip also combine biosensors for the detection of systemic levels of certain investigates and actuators to release bioactive components in response to inadequate concentrations of these investigates.⁷²

Smart polymeric nano-carriers are used in drug delivery applications, bio-separation and other biotechnological applications such as purification techniques.⁴²The food industry has been profited by smart micro- or nanoparticles for including active constituents such as ascorbic acid⁴³ or olive oil⁴⁴in food or antimicrobial polymers such as chitosan to fabricate edible coatings.⁴⁵Information and communication technologies and more specifically data storage devices have been enhanced surprisingly in recent past due to the fabrication of new smart materials. In this way, volume holographic storage would give rise to the future generation of data storage devices, due to their advanced storage capacity and advance transfer rate when compared with actual 2D optical discs.⁴⁶It has been found that, azobenzene chromophores stand by their capacity to induce optical anisotropy when they are incorporated in photo-addressable polymeric materials.⁴⁷

Biomimetic Elastomers:

Biomimetic or biomimicry is the simulated model system which is used to solve the problem of complex human problems⁴⁸and an elastomer is a polymer with visco-elasticity (having both viscosity and elasticity). These materials have very weak inter-molecular forces, generally having low Young's modulus and high failure strain associated with other materials. According to polymeric properties, elastomers are amorphous polymers existing above their glass transition temperature, so that significant segmental motion is possible. Biomimetic is actively used in many fields due to the complexity of biological systems but the number of features is large.

Biodegradable and biomimetic elastomeric scaffolds:

Outstanding mechanical conformity, manageable chemical structure and tunable degradability of biodegradable elastomers currently result a great attention in heart valve tissue engineering. There are a lot of disadvantages of existing therapies which can be overcome by the use of heart valve tissue engineering as a hopeful approach for regenerating and repairing diseased valve tissue.^49-52 This process is directed by renovation of native extracellular matrix- imitative microenvironment with satisfactory biomechanical integrity and by providing the essential biomimetic physical and biological cues.⁵³ Often in vulvular heart diseases, considerable damage of healthy cells as well as disturbance of normal tissue microenvironment are found. So heart valve tissue engineering is important and potential to repair capacity of native valves.⁵⁴ Thus, biomimetic tissue-engineered heart valve concepts that can deliver cells, provide mechanical support and biological signals to encourage valve regeneration in critical requirement.^{52, 53}

Previous reviews have summarized the synthesis and properties of biodegradable elastomers used for tissue engineering,^57-66and their application towards heart valve tissue engineering using several approaches.^67-75 The outcome of heart valve tissue engineering was described as the multi scale hierarchical architecture, scaffold degradability mechanical anisotropic properties and biocompatibility of synthetic elastomeric scaffold-based heart valve tissue engineering approaches.⁷⁶

Biomimetic superelastic graphene-based cellular monoliths:

Graphene based multiple sheets with monolithic structure is an interesting proposal for model application. The capability to continue structural integrity upon huge distortion is crucial to confirm a macroscopic material which functions reliably. It is a challenging issue to accomplish high elasticity in 3D graphene networks. Li et al.⁷⁷reported that the marge of graphene chemistry with ice physics leads to the creation of ultralight and superelastic graphene-based cellular monoliths. The result of mimicking the hierarchical structure of natural cork, materials may tolerate their structural integrity under a load of >50,000 times their own weight and can rapidly recover from >80% compression. The oldest natural materials are exploited and used by human beings is cork.⁷⁸ According to modern structural analysis, interesting results were found to show how nature creates biological cellular materials lightweight yet mechanically resilient. To maximize strength, cellulose nanofibers in the cell walls of wood and cork are closely packed in a highly-ordered manner.⁷⁹ The exceptional biomimetic hierarchical structure also delivers the novel type elastomers with outstandingly high energy absorption ability and good electrical conductivity. Ultralight graphene constructed cellular monoliths which can be superelastic by mimicking the hierarchical structure of cork through a cost-effective freeze manufacture process. Extraordinary carbon-based cellular materials with ultralow density, superelasticity with a tremendously high recovery rate, good electrical conductivity and high efficiency of energy absorption exposed numerous opportunities for a range of biomaterial and technological areas.

Biomimetic Microstructures from Liquid Crystal Elastomers:

One of the interesting and active bio materials are liquid crystal elastomers and networks, used as artificial muscles with covers of elasticity and contractility.⁸⁰ Liquid crystal elastomers have reversible shape shifting characteristics mixing with both rubbers and liquid crystals. The benefit of using of such materials associate with other materials stem from their extensive range of mechanical properties (from soft liquid crystal elastomers to stiff glassy liquid crystal networks), larger actuation amplitude and versatile sources of stimulation, such as heat, UV, and electrical fields. This type of important application in modern science makes them delightful agents for the use in various technological applications such as microelectromechanical systems and responsive surfaces.^81-83 Recently, a lot of procedures have been published to study stimuli-responsive deformations of liquid crystal elastomers, ranging from simple bending actuators to accordion-like ribbons and sophisticated voxelated 3D structures.^84-86 Microfabrication procedures have been working to make different 2D and 3D microstructures from liquid crystal elastomers and liquid crystal networks.^87,88 Usage of micropatterned liquid crystal elastomers – based systems might have different compensations over other described methods such as less external perturbation due to their comprehensive remotely controllable nature and also different mechanical properties, modes, and amplitude of distortion which can be predesigned based on the formulation of the system.⁸⁹

Biomaterial in skin engineering:

Sometimes the use of normal autograft for substituting injured skin, has a greater danger of mortality, lengthy hospital stay and increased expenditure. So, in modern science tissue engineering skin bio-constructs is an active ongoing research field. The use of bioengineered mechanisms of the various skin layers and research for high efficiency has been carried out by different research groups. Such kind of sufficient quantities of biological materials is able to assistance quick wound closure are often the only means to help patients with major skin loss. The extracellular milieu is notifying the progress of a new generation of biomaterials for tissue engineering by the coded molecular and physical information. Previously, several powerful extracellular motivations into cell informative scaffolds have been found, although others remain basically unknown. Till now tissue engineering products have been gained commercial success, not only effective but also cost-effective, presenting a potential contrast between the need for sophistication and comfort of production. Now it is an encouraging interestre-forming extracellular influence in simplified procedures from the reduction of biopolymers into tiny functional areas, to the usage of basic interactions to manipulate destiny of cell. In the near future, these exciting progresses will be able to settle the clinical and commercial pressures on tissue engineering.

In spite of profound development of biological science, the mechanism by which tissues form and heal is still unknown. Developmental biology and other biological disciplines of smart biomaterials work by self-nature mechanisms to repair cell. Such limited information increases the question of how much extrinsic physiochemical evidence is obligatory to assemble endogenous or transplanted cells in constructing a complex tissue and also minimum level of materials complication compulsory for a given task. Clearly, the assessment requires high cost and treatment suggestions for biomaterials method vary with numerous interconnected factors including the form of the device, the approach of distribution, the nature of the cellular component and any controlling implications. Furthermore, the use of materials in endogenous cells into scaffolds avoids the expense and complications related to culture, storage and circulation of cells. Yet, it is important to note that relatively simple materials in combination with a appropriate cellular component can support a high level of tissue association.^90,91The optimization of mechanical and structural features of scaffolds and their potential to direct aspects of cell behavior explains that functional sophistication is not essentially identical with high manufacturing costs.

In fact, there is no ideal composite skin substitute for permanent wound closure. Presently, commercially existing and all the epidermal- and dermal-bioengineered derivatives are essential either multiple stage functioning procedures or autologous skin grafting to accomplish a perfect wound epithelialization. Rapid improvement in tissue engineering and different methods to design a skin substitute biomaterial, including the use of stem cells, may give us confidence that such a derivative may be produced in recent future. Recently, adult stem cell investigation is still in its immaturity but delivers potential applicants for tissue-engineering approaches to regenerate skin for the treatment of extensively burned patients and other serious and chronic skin defects. Excessive scientific, public and business benefits may lead to significant advancement in this field in recent future.⁹²

More advanced biomaterial approaches are just beginning to drip through product-development pathways, but the runaway success of INFUSE⁹³reveals the potential impact of arrangements that make use of growth factor activity. It is promising that the outcome of growth factor administration can be improved enormously with the use of technically simple slow-release schemes, such as delivery using a polymer. This type of reflection may able to establish critical for the determination of complex tissue engineering challenges as well as vascularization. However, the generation of thick or heterogeneous constructs, and even complex organs, will necessitate further novelty in biomaterials research. The exciting possibility of using simple interactions to inspiration cell behavior is also ongoing interest and advance of a range of therapeutics with characteristic or modulating growth factor activity, including designer carbohydrates. Several researchers trying to work in their own ways are actively following simple but effective solutions to tissue engineering problems, like as the ideal of structurally simple, yet functionally complex biomaterials.

Biomaterials in Islet Transplantation:

From last 40 years, although pancreatic islet transplantation has come but still it is usually originating as an experimental performance. Advances in the fields of material science, nanotechnology, immunology, and islet transplantation have been accomplished to shed some light on how we might be able to progress long-term survival and function of pancreatic islet transplants. Type-1 diabetes results from the autoimmune injury of pancreatic β cells. The treatment includes enhanced insulin injections with regular monitoring of blood glucose concentration. Although insulin therapy has advanced quality of life for patients, many patients suffer from hypoglycemic episodes⁹⁴having sub-optimal glycemic control which rises the danger of long-term diabetes complications⁹⁵and occurrence of coma, seizure or death.⁹⁴ Thus, substitutions of islet β-cell mass is an attractive option for patients not only to avoid insulin injection, but also to avoid complications connected type-1 diabetes. Islet of β cells can be replaced either by whole pancreas or by pancreatic islet transplantation. Precisely, pancreatic islet transplantation is not only considerably easier for the patient, but also has variable long-term success.⁹⁴ This is mainly due to the intravascular hepatic transplantation site and resultant blood-mediated inflammatory reactions,⁹⁶ low oxygen tension,⁹⁷ and immunosuppressive drugs.^98-101

β-Cell interactions within its native environment and re-form this islet niche as best as possible in a carrier or capsule as shown in an earlier study,¹⁰² which generates a ‘microenvironment’ for human islets that would encompass not only the islets but also accessory cells, proteins andpossibly local immune suppression housed within a biocompatible material. Such kinds of materials are able to support islets to reconstruct a supportive microenvironment around the transplantation site with required time ultimately be degraded, so, that an appropriate islet micro-organ would persist. These actions deliver a substitution for human islets and must be complemented by efforts in encapsulation, so, that other sources of β cells (e.g., xeno-geneic islets and stem cell–derived β cells) can also evaluate their way to clinical therapy.

Biomaterial in cardiovascular tissue repair:

Cardiovascular disease is one of the anxiety among the people which physically damages the heart, resulting loss of cardiac functioning. Use of appropriate medicine helps patients but treatment of root cause i.e., repairing injured tissues gives patients better results. Recently, cardiac surgeons are using different methods to repair different parts of the heart such as the ventricular septal wall and valves besides heart transplants. This process becomes easy for using a multitude of biomaterials which works to repair and replace of impaired heart tissues. Synthetic and natural biomaterials are the two categories of such kind of biomaterials. For cardiovascular applications using synthetic biomaterials include polymers and metals. Biological sources as like as human donor or collected animal tissues are the source of natural biomaterials.

Future efforts should have an attention on achieving composite materials to take full advantage of the optimal combination of both synthetic and natural biomaterials to advance the overall presentation of implantable materials. This approach will exploit the combined advantages of both types of materials. Composite biomaterials have the potential to solve the current dilemma of having to choose between either synthetics or natural tissues and foregoing the benefits of one or the other material. Given the variety of cardiovascular conditions and resulting variable treatments needed, the wider use of composite biomaterials may be the best approach for improving disease management.¹⁰³

Biomaterials in cardiac patches hybrid engineering:

Before transplantation, cardiac patches in the treatment of heart diseases are completed by planting contracting cells in or onto three dimensional biomaterials. Such kinds of biomaterials are performed as temporary scaffolds by supporting the cells and encouraging their restructuring into functional tissues. Subsequent implantation and full integration within the host, the scaffold degrades leaving a functional cardiac patch on the damaged organ.¹⁰⁴ Recently, it has been originating that operative party of cells into cardiac tissues with morphological and physiological features resembling those in vivo involves a three-dimensional scaffold which exactly mimics the structural, biochemical and mechanical properties of the ordinary heart's extracellular matrix. This is why researchers initially centered on developing technological tools to summarize aspects of this specialized microenvironment.^105-110 Engineered cardiac tissues display elongated and aligned morphology, synchronous contraction and anisotropic transfer of the electrical indication have described previously, when developed on various scaffolds.^108-113 Further, cardiac patches have been employed to progress heart function significantly.^114-117 Though, once the three dimensional cardiac patches have been engineered, in vitro assessment of their quality in terms of electrical activity without affecting their performance is restricted. This may lead to implantation of cardiac patches with restricted or no potential to redevelop the infarcted heart. The cells engineered within the three-dimensional biomaterial may be electro-physiologically inactive, jeopardizing the effectiveness of the treatment. More importantly, the capability to monitor the presentation of these patches and control their role following implantation is exclusively lost.

Recently, it has been described that nano-wire field-effect transistor array, a combined sensor system to manage the native electrical activity within 3D cardiomyocyte concepts.¹¹⁸ Several central system needs remain unmet, in spite of ground breaking advancement e.g., the received data utilization, for interfering and encouraging tissue assembly and confirming appropriate function. To overcome this challenging issue, a conceptually new approach has been introduced to dedicate freestanding electronic network is completed within an engineered tissue and worked to assemble data from surroundings. The electronics can be possible remotely operated when essential to activate the growing tissue, by providing electrical stimulation, by monitoring the release of drugs to affect the engineered tissue or the host within the 3D microenvironment.

The fabrication process involves free standing, scheming porous electronic mesh with multiple electrodes for recording tissue function to deliver electrical stimulation and to affect the engineered tissue or its environment, spatially releasing biochemical factors.¹¹⁹ To obtain least amount of interference with the engineered tissue, thin and porous (>99%)¹²⁰ electronic system was fabricated to allow tissue growth in between the electrodes. To increase effectiveness, on-demand, precise release of drugs, the electroactive polymers were placed on designated electrodes. After that, a dense nano-fiber network containing 3D biomaterial scaffold was combined with the electronics and then planting of cardiac cells to whole the 3D cardiac tissue. At last, the folding of engineered tissue to make a thick, stand-alone, microelectronic cardiac patch comprising embedded elements for sensing, stimulation and regulation.

Biomaterials in tendon and ligament tissue engineering:

Tendon and ligament wounds have high incidence and management of tendon and ligament injuries is technically demanding since the healing response of these soft connective tissues is low. For many future problems, tissue replacement via auto graft and allograft are non-ideal approaches. Although, body can take some of the maximum mechanical loads but adult tendon and ligament have comparatively low oxygen and nutrient obligation, weak regenerative capacity and low cell density. Permanent tissue injury, impaired function and mobility should be happened when the loads overcome a critical threshold. The only alternative to repair of both tissues with their very small self-regenerative capacity is surgical involvement. Surgical intervention means tissue replacement with auto graft or allograft which often be attended with additional difficulties as well as donor site injury, pain and graft failure. Comparatively better solution for it is to fully reestablish the tendon or ligament tissue to its pre-injured state. According to tissue engineering, implanted will progressively renew into a tissue that closely looks like the original tissue and restores functionality. Though, a little is known about these tissues as associated to other musculo-skeletal tissues such as bone, cartilage and muscle, though recent studies have led significant advances and distinct biological differences between tendon and ligament.^121-123Native tendon and ligament anatomy, cellular adherence on biomaterials, matrix construction biomaterial mechanical properties and biomaterial degradation rate are the factors to design tendon and ligament engineering. According to biomaterial point of view, it is important to match of biomaterial properties with the native tendon and ligament structure and purpose which is a crucial consideration. Another important factor is to progress the fields with using combinatorial approaches, like as containing merging braided scaffolds with sponges, merging two materials into a single scaffold, functionalizing a biodegradable surface, or adding mechanical stimulation to aligned cells. Various designs have been approached for engineering tendon and ligament but an ideal engineered tendon or ligament has yet to be arranged. Different significant future milestones of tendon and ligament tissue engineering include improving the strength, biological aspects of the tendon-muscle, tendon-ligament-bone junctions of implanted engineered, developing scaffolds and models that match the rate of scaffold degradation with the rate of tissue in progress, matching with local tendon and ligament elastic and viscos elastic mechanical properties and developing tendon and ligament disease models by tissue engineering. However, technologies full filling such demands necessitate intensive interdisciplinary efforts from biologists, chemists, biomaterials scientists and tissue engineers. This will finally deliver a new and better-quality substitution in repairing damaged tendons and ligaments to thousands of patients.

Stem cells:

There is a growing interest for stem cell research due to the capability of self-renewal and differentiation into specific cell categories, as resulting the using of huge potentials in fundamental biological studies and clinical applications. The most crucial desire for stem cell research is to produce appropriate artificial stem cell culture system which can be able to mimic the dynamic complexity and accurate guideline of in vivo biochemical and biomechanical signals to control and direct stem cell performances. The research of stem cell is related to the progress of identification, isolation, maintenance and differentiation including somatic stem cells, embryonic stem cells and induced potent stem cells have unlocked exciting novel way to advance stem cell-based treatments for different degenerative diseases and producing model schemes for dissecting progressive processes and high-throughput drug transmission.^124-128 Research with stem cell prospective biological and biomedical applications rely on maintaining and distinguishing stem cells appropriately in vitro in a large scale for quite a long time. Yet, preserving undistinguishable stem cells and efficiently monitoring their separation in vitro are still among the extreme challenges which is essential to be addressed before stem cell-based applications can be understood for biomedical and clinical applications such as functional tissue engineering and regenerative medicine^129,130Recently, stem cell and developmental biologists have started a new journey to unravel the complicated molecular circuitry and intracellular signaling pathways modifiable stem cell performances.^125,131,132 It is interesting to note that the simultaneous increased consciousness in stem cell biology on the importance of the native cellular microenvironment through numerous signaling cascades are controlled and combined to control the fate decision of stem cells.^133-135

Ssoluble factors as well as growth factors and cytokines, insoluble biophysical signals as well as cellular connections with the surrounding extracellular matrix, adjacent cell–cell interactions and support cells and interstitial flows in the cellular microenvironment are both critically involved in the regulatory pathway for the stem cell destiny decision.^130,136,137As an example, the quiescent hematopoietic stem cells reside in the bone marrow which can be activated to distinguish into blood and immune cells. The niche cells for hematopoietic stem cells, principally osteoblasts can control intracellular signaling pathways in hematopoietic stem cells critical for the fate decision of hematopoietic stem cells through either straight cell–cell contacts or paracrine signaling.^138-140

The complex, dynamic and heterogeneous native microenvironment monitored the stem cells fate decisions. But also, biochemical factors play significant characters in regulating the self-renewal and differentiation of stem cells, biomechanical signals such as extracellular matrix inflexibility, external mechanical forces and nano topography, essential and can trigger multiple signaling pathways to control the fate of stem cells. Recent developed micro and nano engineering performances have been advanced over the last period, so, to establish a synthetic cellular microenvironment to control the biochemical and biomechanical signals in an extremely combined and controlled manner.

Another powerful performance is micro-contact printing to design the shape and size of single stem cells and stem cell colonies which influences the cyto-skeletal structure and contractility of stem cells to control their behaviors. Micro-fabricated elastomeric micro-post arrangement is hopeful schemes which are modified to accomplish different functionalities such as controlling extra cellular matrix rigidity, measuring traction forces and applying native and global forces to stem cells. The combination of such micro, nano engineering with other current micro, nano-scale devices or performances leads o deliver a complete control of the native cellular microenvironment for stem cells at the sub-cellular or cellular resolution to straight their behaviors.

In spite of current success by using micro, nano engineering tools to generate well-controlled stem cell culture platforms, their applications toward large-scale stem cell culture still have approximate restrictions. Most of the systems applied in this area are more suitable for single-cell analysis or high-throughput screening, rather than for scalable stem cell culture and production. In addition, these methods are still far away from being broadly adapted in common biological laboratories. Applications and procedures of these schemes still necessitate precise engineering expertise. Thus, future advance of micro engineered synthetic cellular microenvironment for stem cell investigation will necessitate closer collaborations between stem cell and developmental biologists, tissue engineers, micro, nano engineering scientists. In the upcoming days, it would be extremely desirable to advance facile, standard and automatic systems using micro, nano engineering performances to control stem cell microenvironment.

Immunoisolating microcapsules:

For implantation purposes of cells, immunoisolation based on enveloping the cells in a biocompatible and semi permeable membrane allows diffusion of crucial nutrients and therapeutic molecules but avoids deleterious effects of the humoral and cellular part of the host immune system.^141,142 This interesting procedure is planned for the distribution of cell based therapeutics where native and minute-to-minute release of the active molecule is desired for active treatment. Encapsulation of existing cells for the release of biological therapeutics is under research for a variety of diseases such as diabetes,¹⁴³ neurological diseases,^144-147 and various forms of human cancers.^148-150 Microencapsulation is common and applied technology of immunoisolation, therapeutic cells in spherical beads completed of alginate polymers¹⁵¹using different encapsulation procedures such as electrostatic bead generator, jet cutter, vibrating nozzle and coaxial air driven droplet generator.¹⁵² Often favored beads are sphere-shaped over discs or tube like structure because of the promising surface-to-volume ratio that facilitates nutrition of the cells and the release of therapeutic agents.¹⁵¹ Microcapsules is preferable for another reason because it is comparatively of small size that permits for transplantation in many sites without interference with the receiving organ.¹⁵¹ The last on is an imperative consideration for example in the treatment of brain tumors where implantation of microencapsulated cells constructing anti-tumor agents has been proposed as an effective approach to delete leftovers of malignant cells.^152,153 Aggressive brain tumor cells are unbearable to identify and remove during surgery and are a major cause of morbidity.

For the use of brain tumor treatment, microcapsules should encounter a number of requirements as like as key features in scheming immunoisolating microcapsules which is avoiding protrusion of cells from capsules. Furthermost conventional alginate encapsulation schemes do not gather this prerequisite, as protrusion of cells is more the rule than an exception. Protrusion of cells is connected with rejection and fibroticreplies followed by necrosis of the therapeutic cells, which eventually leads to graft failure.^154,155another problem is that the therapeutic cells based on cell lines may arrange tumors themselves when they leak out of the capsules. This is a major safety obstacle avoiding the application of cell encapsulation technology in the clinic. Therefore, cell based therapy requires a system in which protrusion of cells is prohibited.

Application of alginate-microencapsulated healing cells is a possible method for diseases that necessitate a native and constant supply of therapeutic molecules. Most conventional alginate-microencapsulation schemes are associated with low mechanical constancy and protrusion of cells which is associated with higher surface roughness and restricts their clinical application. In specific with encapsulated therapeutic cell lines, extension of these cells from the capsules may lead to tumor formation. Bhujbal et al.¹⁵⁶described a novel microencapsulation scheme which strongly decreases cell protrusion. Numerous biocompatible alginates were applied to ease progress and survival of therapeutic cells in the core of the capsules while damaged cells escaping from the core of multilayer capsule. Till now, studies are continuing in determining the efficacy of this system in pre-clinical in vivo models.

Femtosecond laser micromachining:

Femtosecond laser micromachining of transparent materials are high-class rewards over other photonic-device fabrication techniques. At first, the nonlinear nature of the absorption restricts any encouraged deviations to the focal volume. The combination of spatial confinement with laser-beam scanning or sample material alteration changes it conceivable to micromachine geometrically complex structures in three dimensions. Second, the absorption process is not dependent of the material, allowing optical devices to be fabricated in compound substrates of various materials. Third, femtosecond laser micromachining is useful for the construction of an ‘optical motherboard’, where all interconnects are fabricated separately, before/after bonding numerous photonic devices to a single transparent substrate. The probable use of femtosecond laser micromachining for either to eliminate materials or to modify properties of a material can be applied to both absorptive and transparent materials. Over the last decade, such kind of procedure has been used in a extensive range of applications from wave guide fabrication to cell ablation. Femtosecond laser micromachining was first established in 1994, when a femtosecond laser was working to ablate micrometresized features on silica and silver surfaces.^157,158 Within, ten years the resolution of surface ablation has been enhanced to allow nanometer-scale precision.^159,160There are many articles on femtosecond lasers,^161,162 nonlinear processes,^163-165 optical breakdown,^163,165surface micromachining,^166,167 and the history of femtosecond laser micromachining.¹⁶⁸

Application in nanosurgery:

For quite a long-time laser is used for discerning aim of structures and cells¹⁶⁹and currently the effort involved pulses with periods in the range of picoseconds or longer.¹⁷⁰As a result of these long pulse periods, huge quantity of energy is obligatory to encourage a material to change. Although sub-wavelength resolution has been described¹⁷¹ heating and shockwave propagation leads to collateral harm.¹⁷² In biological aspects, control over the energy deposition is vital. The previous study exhibited that for cells even a slight rise in temperature leads to cell death.¹⁶⁵ Femtosecond laser pulses make accurate energy delivery possible subsequent in clear, extremely localized scratches in biological samples.¹⁷³ The capability of selectively ablate a portion using femtosecond laser pulses was initially confirmed in the procedure of chromosome division¹⁷³and later prolonged to sub-cellular organelles^174-176. Consequently, femtosecond lasers have recognized themselves as vital apparatuses in biology with a extensive range of applications, containing selective neurosurgery for performance analyses of the neuronal network.^177,178

Ultrafast lasers:

The novel appearances of ultrafast lasers as like as picosecond and femtosecond lasers have unlocked a new horizon in materials processing which can be used as ultrashort pulse widths and enormously high peak intensities. Therefore, ultrafast lasers are currently providing efficiency extensively for both fundamental research and practical applications. The use of ultrafast lasers for materials processing was first reported in 1987 by Srinivasan et al.¹⁷⁹Ku¨per and Stuke.¹⁸⁰ According to their description, use femtosecond ultraviolet excimer lasers leads the clean ablation of polymethyl methacrylate nearly without the formation of a heat-affected zone. The ablation threshold was found lesser sufficient than that for nanosecond laser ablation. Such kind of applied experiments have a significant influence and the investigation in this field which was expanded quickly in the 1990s. Furthermore, the progress of the chirped-pulse amplification procedure in Ti-sapphire reformative amplifiers¹⁸¹ discharge active femtosecond pulses without inducing damage or unwanted nonlinear effects in the amplification medium. One of the significant features of ultrafast laser processing is that it decreases heat diffusion to surrounding areas of the processed zone.¹⁸²this feature is improved to the high-quality micro fabrication of soft materials as well as biological tissues¹⁷⁷ and hard or brittle materials as well as semiconductors and insulators¹⁸³ without heat-affected zone formation. Further, suppression of heat diffusion to the surroundings improves the spatial resolution for nanoscale processing.¹⁸⁴ Another important characteristic feature of ultrafast laser processing is that nonlinear /multiphoton absorption which induces strong absorption even in materials that are transparent to the ultrafast laser ray.^185,186 Multiphoton absorption allows not only surface processing,¹⁸⁷ but also three-dimensional internal micro fabrication of transparent materials as like as glass and polymers.^188-191 In 1996, Davis et al.¹⁸⁸ and Glezer et al.¹⁸⁹ established this field and presented correspondingly optical wave guide writing and development of nanovoid arrays inside glass. Recently, internal micro fabrication is extensively functional to the construction of photonic devices and biochips.^192,193 In 2001, it was described that multiphoton absorption advances spatial resolution to exceed the diffraction limit, due to the non-linearity combined with the threshold effect.¹⁹⁴Careful control of the laser power and scanning speed permitted a minimum fabrication resolution of 18 nm to be accomplished.¹⁹⁵ One of the main application fields of this feature is two-photon polymerization, for the construction of photonic crystals,¹⁹⁶ micromachines¹⁹⁷ and biochips.¹⁹⁸ In the 2000s it has been projected that ultrafast laser irradiation at intensities near the ablation threshold forms nanoripple structures on numerous materials with periodicities much smaller than the wavelength.^199-202 Regular arrays of conical microstructures were also produced on Si by irradiation with an ultrafast laser beam in a halogen atmosphere e.g. SF₆ or Cl₂.^203,204 The surface structures formed display unique properties of anti-reflectivity, super-hydrophobicity and infrared absorption.

Commercial Medical applications:

In medical field, ultrafast laser has an important application for the fabrication of coronary stents using for the minimally invasive treatment of arteriosclerosis as an alternative to bypass operations and characteristically stents are fabricated from stainless steel or shape memory alloys. It is important to post-process these materials chemically to understand the required properties. In addition with good application, there have been some disadvantages with stents related medical problems such as the risk of restenosis and incomplete biocompatibility. To attain for better biocompatibility, Mg-based alloys or unusual biopolymers are used. Yet, for stent production, these materials also suffer from difficulties, necessitate a poorly well-known post-processing procedure and to react powerfully to thermal loads. Ultrafast laser micromachining can overcome these difficulties since it produces little debris such as slight heat-affected zone. The earlier reports have illustrated a medical stent fabricated from a bioresorbable polymer using femtosecond laser ablation without post-processing²⁰⁵ that is presently complete for practical use.

Additional application in the therapeutic field is laser-assisted in situ keratomileusis, frequently mentioned to as LASIK, which is a refractive surgery used to correct myopia, hyperopia and astigmatism with the help of laser.²⁰⁶ A scheme equipped with a femtosecond laser to arrangement corneal flaps (Femto-LASIK) is now commercially existing and is more accurate and expectable than a conventional mechanical microkeratome.²⁰⁷

Conclusion and future prospects:

Biomaterial research have brought revolutionary change in combined life science giving equal importance to material and engineering sciences as the foundation of the field. Advances in engineering such as nanotechnology contribute significantly in biomaterial designing and have allowed fabrication of materials with increasing complex functioning. The new generation bio-inspired materials will possibly be the advance of ‘smart’, multifunctional nanoparticles or transplants for usage in our bodies. These complex materials would accept many inputs from chemical and physical stimuli in enhancing their performance. Such advance biomaterial will be able to target desired anatomical areas, monitor health, and aggressively interfere in biological crises. Materials that selectively contribute with precise cell populations for the use in diagnostic or therapeutic applications, may even be formed by considering and finally binding the dynamic signals provided by specific cell types like as stem cells to modify in situ, or accumulate in situ, complex devices or materials from simple input templates. Elsewhere the devices and materials themselves, biological inspiration may revolutionize the approaches used to produce and modify raw materials in the chemical and materials industries. For example, living plants can procedure a large category of liquids and materials in huge quantities than are produced by mankind commercially, but they can do without the energy cost or waste streams which are different from chemical industry. According to the lessons from nature may not only permit the synthesis of new chemicals but also suggestively decrease the costs and environmental impacts linked with the production of present chemicals and drugs. The biomaterials field with respect to academic and industrial features is quickly becoming unrecognizable in terms of its present designation. The field will demand to be redefined to include materials which direct biology and those whose design and functions are encouraged by natural materials, future generations of biomaterials are likely to be critical components in many facets of current society.

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Received on 25.06.2017 Modified on 11.07.2017

Asian J. Research Chem. 2017; 10(4):441-453.

DOI:10.5958/0974-4150.2017.00073.6