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Recent Advances in Biomaterials Science and Engineering Research in India: A Minireview Sunita P. Victor,‡ Shivaram Selvam,‡ and Chandra P. Sharma*

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Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Satelmond Palace Campus, Poojappura, Trivandrum 695012, India ABSTRACT: Biomedical research in health innovation and product development encompasses convergent technologies that primarily integrate biomaterials science and engineering at its core. Particularly, research in this area is instrumental for the implementation of biomedical devices (BMDs) that offer innovative solutions to help maintain and improve quality of life of patients worldwide. Despite achieving extraordinary success, implantable BMDs are still confronted with complex engineering and biological challenges that need to addressed for augmenting device performance and prolonging lifetime in vivo. Biofabrication of tissue constructs, designing novel biomaterials and employing rational biomaterial design approaches, surface engineering of implants, point of care diagnostics and micro/nano-based biosensors, smart drug delivery systems, and noninvasive imaging methodologies are among strategies exploited for improving clinical performance of implantable BMDs. In India, advances in biomedical technologies have dramatically advanced health care over the last few decades and the country is well-positioned to identify opportunities and translate emerging solutions. In this article, we attempt to capture the recent advances in biomedical research and development progressing across the country and highlight the significant research work accomplished in the areas of biomaterials science and engineering. KEYWORDS: biomedical research, tissue engineering, drug delivery, surface modification, biosensors, theranostics

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INTRODUCTION The biomedical device (BMD) industry, which comprises devices made of natural and synthetic biomaterials, has witnessed exponential growth over the last five decades and is poised to maintain this trend in the near and distant future.1 For instance, the global market for BMDs is expected to reach an estimated $342.9 billion by 2021 with an estimated average growth rate of 4.6% per year.2 In India, the BMD industry is presently valued at USD 5.2 billion with about 800 μBD manufacturers in the country. With an average turnover of Rs. 450−500 million,3 the Indian BMD market is witnessing steady growth and is estimated to grow to USD 50 billion by 2025.4 This rapid growth is attributed to the fact that BMDs have seen increased adoption because of noted improvements in device design and function which enhances their performance and reliability thereby raising standards of living and improving the quality of life for patients all over the world.1 Although newer generation BMDs have augmented device efficacy and safety deemed worthy for clinical applications, there are several shortcomings that still need to be addressed for improving device performance in vivo.1 The development of new kind of biomaterials for tissue engineering applications, improved surface modifications and biocompatible coatings for implantable medical devices, micro/nano-based technologies for fabrication of point of care (POC) devices and biosensors, and localized and targeted drug delivery systems are some of the strategies that are currently been explored for augmenting clinical performance of BMDs in vivo.1,5 © XXXX American Chemical Society

Tissue engineering involves the combination of mammalian cells with biocompatible polymeric materials to yield functional tissue/biomaterial constructs to repair or replace damaged tissues in vivo.5−7 Currently, most biomaterials employed for this objective are based on off-the-shelf materials that were initially used for consumer applications.5 Hence, there lies a significant need for developing biomaterials that employ rational design approaches with novel surface chemistries to enhance cellular activities, including cell adhesion, proliferation and differentiation, improve biocompatibility, and confer electrical conductivity for fabrication of complex tissue constructs. Along similar lines, medical implants that function to restore damaged or support existing structures in the human body elicit a host inflammatory response that severely affects their performance and function in vivo.1 Research efforts in the surface engineering of implants to achieve desired functionalities and enhance bio- and hemo-compatibility could greatly aid in the mitigation of host inflammatory responses which in turn will prolong the lifetime of the implanted device in vivo.8 Another thrust area is the growing demand for design and development of novel POC devices and biosensor platforms for rapid real-time detection of diseases for immediate decision making and effective clinical management of patients.9 These Special Issue: Biomaterials Science and Engineering in India Received: February 26, 2018 Accepted: May 21, 2018 Published: May 21, 2018 A

DOI: 10.1021/acsbiomaterials.8b00233 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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Specifically CPs including nanocrystalline HA, calcium deficient HA (CDHA), tricalcium phosphate, amorphous calcium phosphate (ACP) tetracalcium phosphate developed from natural materials such as egg shell and coral Goniopora have demonstrated favorable properties for bone applications.14 For example, coralline HA loaded with growth factors could significantly accelerate bone formation in vivo.15 In another study nanopowder cement based on HA and calcium sulfate (CS) has been evaluated as a bone substitute for cranioplasty.16 These powders were functionalized with bone morphogenetic protein-2 (rhBMP-2) and zoledronic acid (ZA) to endow them with osteoinductive properties. The potential of rhBMP-2 and ZA to enhance regeneration of bone has been evaluated and the bone formation in vivo measured using a critical rat cranioplasty model. The control group revealed least amount of mineralized volume at the defect site based on Masson’s trichrome stained decalcified bone sections and Alizarin stained undecalcified bone sections. The mineralization pattern and differences among the groups showed that functionalization of NC by rhBMP-2 and ZA enhanced its osteoinductive properties.16 Similarly, it has been observed that an injectable biphasic carrier containing CS and HA loaded with rhBMP-2 and ZA through physical entrapment or chemical binding initiate osteogenic differentiation of mesenchymal progenitors.17 The ZA attached to the carrier provides protection to the newly developed bone and the biphasic microporous carrier that sets in situ makes it suitable for controlled release of encapsulated drug. In a previous study, Raina et al. suggests a possible mechanism for bone formation synergistically supervised by bone active proteins leaking from a bone defect and enhanced by the presence of biomaterials such as HA and CS.18 Clinically extensive bone formation has been observed in the muscle surrounding HA-CS in as minimum as 6 weeks postsurgery owing to their inherent osteopromotive properties.18 Additionally pullulan hydrogel scaffolds reinforced with nanocrystalline HA led to enhancement of compressive modulus and induced osteoconductive behavior by pore wall mineralization.19 Macroporous HA scaffolds possessing interconnected oval shaped pores were found to have enhanced cellular functionality combined with the ability to support osteoblast differentiation.20 Also, nanocomposites containing HA and zinc oxide employed as restorative glass ionomer cement demonstrated unique properties necessary for hard tissue applications.21 Likewise, attempts have been made to develop functionally graded HA-alumina-zirconia biocomposite, which demonstrated enhanced bulk toughness, cellular adhesion, and unparalleled surface bioactivity.22 A wide range of natural and synthetic biopolymers have also been investigated for bone tissue engineering applications. Particularly, silk fibroin, a natural high-molecular -weight protein obtained from silk worm species, possesses robust mechanical properties, tunable biodegradability, and excellent biocompatibility that are promising as orthopedic biomaterials for bone repair and regeneration.23 In addition, silk can be manipulated into various material formats such as, films, scaffolds, fibers, and sponges, which are advantageous for specific bone applications. For instance, patterned silk films have been investigated to study the alignment and osteogenic differentiation of human mesenchymal stem cells (hMSCs) as a biomimetic approach for the design and engineering of cortical bone lamellae.24 Results showed that the grooved silk films successfully induced osteogenic differentiation and robust alignment of hMSCs in vitro, which were similar to that

devices are reliable, cost-effective, and offer unparalleled ease of use resulting in improved patient safety and overall clinical outcome.9 Another area of interest which is gaining increasing importance is the localized or site-specific delivery of pharmaceutics on-demand using smart biomaterials for efficient and safe delivery of drugs at a clinically relevant concentration to achieve maximal therapeutic effect.10 In this quest, numerous polymer-based drug delivery systems have been extensively explored for potential clinical applications such as cancer and arthritis. Biomedical research in India has shown a strong growth trajectory over the past several decades and advancements in this regard has vastly bettered health care infrastructure, reduced disease burden, and reformed the economic and social conditions of the poor in the country. As an example, the number of publications related to biomaterials research has risen steadily over the past few years in the country (Figure 1)

Figure 1. Gradual increase in the number of publications from India related to biomaterials research over the past few years. Source: www. ncbi.nlm.nih.gov/pubmed with search keywords “biomaterials” and “India”.

and standing at the forefront, the Sree Chitra Tirunal Institute for Medical Sciences and Technology, Poojappura, Trivandrum has been instrumental in developing and commercializing technologies for a number of devices including, mechanical tilting disc heart valve prosthesis (an estimated 100,000 patients have been implanted with these heart valves), blood bags (annual production of nearly 40 million bags), membrane oxygenators, hydrocephalus shunts, vascular grafts, dental and hydroxyapatite-based bone materials.11 Furthermore, SBAOI and STERMI, stated in 1986 and 2007 respectively, have played a significant role in the emergence of biomaterials science and engineering in India with their annual meetings workshops and other activities.12 In recent times, numerous other national and private research institutions have been established to explicitly devote and actively promote biomedical research in the country. In this minireview, we highlight the research progress made in the field of biomaterials science and engineering in India over the past few years and present a snapshot of some of the significant works accomplished to address the engineering and biological challenges relevant to BMDs discussed above.

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TISSUE ENGINEERING Bone. An array of biomaterials, including synthetic and natural ceramics, polymers, and composites, has demonstrated potential osteoconductive properties cuing toward osteogenic differentiation critical for bone tissue engineering.13 Several calcium phosphate (CP)-based materials in the form of bone void fillers, nanopowders, coatings, composites, and scaffolds have been evaluated for bone engineering applications. B

DOI: 10.1021/acsbiomaterials.8b00233 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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ACS Biomaterials Science & Engineering found in native cortical bone.24 In another study, acellular silk fibroin scaffolds were employed in an attempt to qualitatively compare the extent of osteogenic generation in a critical size rat cranial defect model.25 Results indicated that nonmulberry Antheraea mylitta silk, which naturally possessed cell binding RGD motifs, demonstrated better osteogenic characteristics compared to RGD lacking mulberry Bombyx mori fibroin scaffolds.25 Furthermore, silk fibers have been exploited as fillers for microfiber reinforcements toward bone repair.26 The silk microfiber-reinforced three-dimensional scaffolds exhibited low immunogenicity, possessed matrix stiffness and surface roughness resembling that of native bone, and more importantly, enhanced hMSC differentiation compared to control silk sponges in vitro.26 Additionally, composite biomaterials that synergize beneficial characteristics of multiple components while complementing their individual shortcomings have also been designed and developed as artificial bone grafts. For instance, attempts have been made to further improve the mechanical properties of pure silk fibroin by reinforcing silk scaffolds with carbon nanofibers,27 HA,28 and synthetic polymers such as, polycaprolactone (PCL).29 and poly(vinyl alcohol) (PVA).30 Likewise, chitosan, gelatin and alginate based biocomposites have also been extensively investigated for bone tissue regeneration in vivo.31−33 Taken together, results from these studies show that composite biomaterials possessed superior mechanical properties compared to single component matrices and demonstrated intrinsic osteogenic potential favorable for various load bearing applications. Cartilage. Composite biomaterials have also been availed for the engineering of an artificial cartilage.34 Particularly, physiochemically controlled chitosan-agarose-gelatin (CAG) cryogel scaffolds have been designed and fabricated to mimic the functionality of native cartilage.35−37 CAG cryogels are prepared via “cryogelation” process whereby the polymer blend, which contains dissolved polymers and cross-linker, is poured in precooled syringe molds and incubated at −12 °C for 16 h to generate macroporous scaffolds with high pore interconnectivity.35 Chondrocytes cultured on CAG cryogel matrices formed neo-cartilages within 6−8 weeks in vitro and resembled native cartilage, as evidenced through histological and biochemical analyses.35 Furthermore, implantation of acellular CAG cryogel scaffolds for regeneration of subchondral cartilage defects in a rabbit model demonstrated that CAG scaffolds played a significant role in cartilage regeneration and that the regenerated tissue exhibited good integration with adjacent native cartilage and subchondral bone during the 8-week time period.36 In addition, studies were also performed to investigate whether CAG cryogel scaffolds in combination with allogenic chondrocytes and bioactive molecules demonstrated enhanced repair of subchondral cartilage defects in vivo.37 Unsurprisingly, the integrated approach of using cell-seeded scaffolds along with bioactive molecules demonstrated more rapid regeneration of cartilage tissue compared to acellular scaffolds with or without incorporation of bioactive molecules that was collected from conditioned media of chondrocytes in vitro.37 Hydrogel composites based on silk and agarose have also been studied for use in cartilage tissue repair and creation of functional cartilage constructs.38,39 Studies showed that silkagarose hydrogels provided a stable structural and mechanical microenvironment for maturing chondrocytes and were highly supportive of cartilage extracellular matrix (ECM) deposition in vitro.38 Along similar lines, porous silk-chitosan composite

scaffolds, examined for its ability to support chondrogenesis in vitro, demonstrated good support for chondrogenic proliferation and differentiation of rat MSCs with histiotypic features typical of neocartilageous tissue.39 Vascular. Electrospinning is the common methodology employed for the development of artificial vascular grafts.40 In this process a polymer melt or solution is drawn under a high voltage difference to produce nanofibers.40 In this regard, synthetic polymers have been routinely employed for their high strength and durability in the fabrication of small dimeter vascular conduits (SDVCs). For instance, poly(hydroxy butyrate-co-hydroxy valerate) (PHBV)-PVA based SDVCs (1 × 102 mV/mm of tissue and exist in the cytoplasm or extracellular space of cells.69 In clinical settings, exogenously applied EF has been shown to mitigate pain associated with numerous acute and chronic conditions and has been employed to rehabilitate damaged or disabled tissues in the neuromuscular system, including spinal cord injury, paralysis, and cardiovascular diseases.70,71 Numerous studies have also shown that cell behavior can be influenced under an exogenously applied EF in vitro.72 Hence, a lot of interest has been directed to the development of electrically conducive biomaterials that would impel cellular behavior toward tissue differentiation and E

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that T1HC coated substrates amplified adhesion and growth of human periodontal fibroblast cells compared to uncoated Ti alloy surfaces.85 Along similar lines, HA−titanium dioxide (HATiOx) nanohybrid composite was coated on titanium substrates by electrophoretic deposition to confer hydrophilic surface characteristics for enhancement of cell adhesion and proliferation.86 Similarly, plasma sprayed nano/micro ceramic oxide coatings based on alumina and zirconia have also been attempted to evaluate its biocompatibility and antibacterial activity on Ti alloy surfaces in vitro.87 In another study, silk sericin protein was surface-immobilized on Ti surfaces and functionalized with RGD peptide motifs to influence the osseointegration process around Ti implants in vivo.88 Studies showed that sericin immobilized Ti surfaces enhanced adhesion, proliferation and differentiation of osteoblast cells with upregulated expressions of bone sialoprotein, osteocalcin, and alkaline phosphatase in vitro.88 Polymer PCL scaffolds have also been surface modified to boost their osteoconductive potential for bone tissue engineering applications.89 For instance, electrospun nano-, micro-, and multiscale PCL fibers were subjected to low-pressure argon and nitrogen plasma treatment to introduce polar groups for increased surface hydrophilicity.89 Surface plasma-treated PCL fibrous scaffolds showed remarkable cell adhesion properties and convincingly influenced MSC differentiation toward osteogenic lineage in vitro.89 Furthermore, cells in osteoblast lineage demonstrated maximal alkaline phosphatase activity in 14 days and confirmed biomineralization activity on plasmatreated scaffolds in vitro.89 Surgical Sutures. Surgical sutures are arguably the most widely used medical products availed for wound closure in clinical applications.90 On account of this fact, the suture material employed should possess optimal physicochemical characteristics that are crucial for delineating its performance in vivo.90 Many polyester based synthetic polymers have been examined for their suitability as suture materials owing to their high tensile properties.90 In this regard, PLLA fibers are one of the most commonly used as they possess high crystallinity and rigidity, and a degradation behavior that can be altered preferentially to match the biological milieu of host tissue.91 Furthermore, absorbable PLLA suture materials are amenable to the incorporation/coating of various drugs/drug-loaded polymers that confer them antibacterial and antifungal activities that enhance wound healing at the site of injury.91,92 For example, various antibiotic-loaded chitosan and alginate based polymers have been coated on PLLA suture materials and their drug-eluting and antibacterial properties in vitro.92 Polypropylene (PP) monofilaments have been evaluated as suture materials by grafting them with monomers that are amicable toward drug immobilization.93,94 For instance, acrylonitrile-grafted PP monofilaments prepared via preirradiation method demonstrated good tensile strength and physiocochemical characteristics as a function of the degree of grafting.93 Moreover, subsequent conversion of nitrile groups to carboxyl groups yielded tetracycline drug immobilized sutures which favor wound healing after suturing procedures.95 Drug-immobilized sutures exhibited continuous release of drug over a period of 5 days and displayed a zone of inhibition against both Gram-positive and Gram-negative bacteria in vitro while demonstrating tissue compatibility and bacterial growth inhibition in an infectious rat model in vivo.96 In a similar design, drug immobilized PP monofilaments grafted with 1vinylimidazole (VI) demonstrated good elongation properties

The interplay of pANL substrate conductivity, EF stimulation and ECM coating toward osteogenesis of hMSCs was studied in vitro (Figure 2).77 It was established that hMSCs cultured on EF stimulated collagen/sulfated hyaluronan coated pANL substrates demonstrated enhanced osteogenic differentiation with more calcium deposition and accelerated ALP activity along with increased expression of osteogenic markers such as Runt-related transcription factor 2, collagen type I and osteopontin.77 Furthermore, EF stimulated hMSCs displayed different morphological features compared to nonstimulated controls. In another approach, the role of an externally applied magnetic field to drive direct differentiation of hMSCs to an osteogenic lineage was investigated in vitro.78 In this work, hMSCs were cultured on HA-Fe3O4 magnetic substrates under the influence of a static magnetic field (SMF).78 Results showed that SMF exposure increased cell viability and expressed upregulation of late osteogenic markers such as osteocalcin and osteopontin. In addition, matrix mineralization and calcium content was enhanced in the presence of SMF, even in absence of osteogenic supplements in culture medium. Overall, these studies highlight the potential of integrating substrate conductivity and external biophysical stimulations to modulate cell fate and function for various biomedical applications.

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ENGINEERING BIOMEDICAL DEVICES FOR POTENTIAL APPLICATIONS Surface Modification of Implants. Surface engineering of implant surfaces is critical for enhanced biocompatibility and osseointegration of the implanted material with bone and surrounding tissues.8 In this regard, metal alloys, such as magnesium and titanium (Ti) alloys, possess good mechanical properties and bioinertness and have been successfully used for various orthopedic and dental applications.79,80 Magnesium alloys possess good elastic moduli matching that of native bone (10−40 GPa) and its degradative characteristics can be tailored to conform with the healing rate of bone.81 Nevertheless, magnesium implants are associated with high corrosion rate that could lead to production of hydrogen gas pockets, hemolytic reactions and mechanical disintegrity at the implant site in vivo.82 To address these concerns, strontium-doped zinc calcium phosphate (SZCP) coating has been reported to enhance corrosion resistance and biocompatibility of resorbable magnesium alloys.83 Results showed that SZCP surface coating augmented biomineralization characteristics, improved corrosion resistance and demonstrated less cytotoxicity of AZ31 magnesium alloy in vitro.83 Medical-grade titanium alloys with unmodified surfaces contain an oxide layer that protects it from corrosion under normal physiological conditions but is associated with a net negative charge that is nonconducive for cell adhesion and proliferation in vivo.84,85 Hence numerous strategies have been employed to alter the surface of Ti implants to promote cell attachment and growth for improving its biointegration with host tissue in vivo. Toward that end, surface modification of Ti alloy discs was performed via a two-step process in which hydroxyl groups were first introduced on the alloy surface via heat and alkali treatment, following which silanization with (3aminopropyl)triethoxysilane yielded a surface containing free terminal amine groups that can be utilized for biofunctionalization procedures.84 This technique has been employed to bioconjugate type I human collagen (T1HC) on to Ti surfaces via carbodiimide coupling reaction to improve cell adhesion characteristics of modified Ti surface.85 Results demonstrated F

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ACS Biomaterials Science & Engineering and exhibited antimicrobial activity against Esherichia coli in vitro.94 Although radiation grafting produced PP based sutures with overall good mechanical characteristics, it inevitably leads to a slight loss in mechanical strength of fabricated sutures.97 To overcome this issue, PP sutures grafted with acrylic acid via plasma-induced graft polymerization were developed for clinical applications.97 The fabricated sutures were modified by immobilizing chitosan and tetracycline/nanosilver to prevent scar formation and bestowing them with antimicrobial properties.97 Results showed that modified PP sutures displayed controlled drug release characteristics and antimicrobial activity in vitro while demonstrating excellent tissue compatibility for a period of 30 days in rats in vivo.97 Adopting a similar approach, poly(ethylene terephthalate) (PET) surgical sutures were developed and functionalized with carbon dioxide plasma treatment for subsequent immobilization with bioactive nanosilver nanogels and chlorhexidine.98 Unsurprisingly, nanogel-immobilized PET sutures offered excellent antimicrobial activity against both E. coli and Staphylococcus aureus in vitro and demonstrated faster wound healing and antimicrobial properties over a period of 72 h in mice in vivo.98 Wound Dressing Materials. An ideal wound dressing material (WDMs) should possess adequate flexibility and mechanical strength, maintain a moist environment at the wound interface, aid in the removal of exudates from wounds and above all, act as barrier against microbes and allow good gaseous exchange at the wound surface.99 In this regard, various hydrogel-based WDMs have been designed and developed to enhance reepithelialization and promote healing of skin wounds. For instance, pectin-gelatin (PG) based hydrogel matrices loaded with antimicrobial aloe vera (AV) and curcumin (Cur) on nonwoven cotton fabrics have been engineered as composite wound care devices.100 Results showed that the composite WDMs were cytocompatible and exhibited antimicrobial activity in vitro, while histological examination of excised tissues demonstrated rapid healing within 8 days in a mouse excisional splint wound model in vivo.100 In a similar approach, composite WDMs based on PG hydrogels loaded with broad spectrum antibiotic ciproflaxin or antimicrobial silver nanoparticles (nAg) were fabricated and compared with a commercially available dressing material, Bactigras.101 Quite remarkably, both PG-based composite WDMs demonstrated a good wound healing rate comparable to that of Bactigras, and in addition, unlike Bactigras, demonstrated organized collagen deposition and neovascularization in a mouse full thickness excisional wound model in vivo.101 Chitosan is another natural polymer that has antibacterial, anti-inflammatory and hemostatic properties that makes it favorable for wound healing applications.99 In this context, a multifunctional sponge based on chitosan-hyaluronic acid (ChHyA) matrix was evaluated for antifibrinolysis and antibacterial potential for management of wounds in patients with hyperfibrinolytic conditions.102 In vitro studies showed that the engineered dual functional bilayered sponge demonstrated antibacterial property to clinically relevant pathogens while exhibiting antifibrinolytic activity against streptokinase-induced clot lysis.102 Along similar lines, a bilayered WDM based on Ch-HyA matrix with antimicrobial and MMP inhibition characteristics was developed to facilitate accelerated wound closure.103 Furthermore, Ch-HyA-based WDM loaded with nAg was fabricated for treatment of diabetic foot ulcers.104 Applying a similar strategy, chitosan-nanofibrin (Ch-nF) and

Ch-G-nF-based composite bandages were developed for treatment of burn wounds.105,106 The prepared composite bandages exhibited good physicochemical properties and biocompatibility characteristics in vitro. Furthermore, studies showed that the composite bandages promoted collagen deposition and reepithelialization within 2 weeks compared to experimental controls in a rat wound healing model in vivo.105,106 To circumvent the incorporation of an antimicrobial agent, to avoid complications associated with antibiotic resistance and delayed wound healing, chitin and chitosan based WDM loaded with zinc oxide (ZnO) nanoparticles (Figure 3), which display antibacterial characteristics like nAg,

Figure 3. Schematic representing chitosan composites for wound dressing; in vitro and in vivo evaluation. Reproduced with permission from ref 108. Copyright 2012 American Chemical Society.

have been developed to provide a cool moisture-rich environment as well as to impart antimicrobial activity to treat a wide range of wound conditions.107,108 A bilayer composite cryogel composed of synthetic polyvinylpyrrolidone (PVP) and gelatin incorporating microparticles loaded with iodine(I) and human fibrinogen has been developed as a WDM.109 The top PVP-I layer served as an antimicrobial sheet, whereas the gelatin-fibrinogen bottom layer imparted elasticity and enhanced wound healing characteristics.109 In vivo studies on a full thickness wound defect rabbit model demonstrated that the fabricated cryogel WDM exhibited better and faster skin regeneration at the wound site comparable to commercially available skin regeneration scaffold, Neuskin-F. 109 In another approach, antibiotic tetracycline loaded Ch−PEG-PVP gel on cotton fabric showed promised as a scar preventing WDM.110 In another study, electrospun PVA−PVP nanofibrous membranes loaded with antibiotic ciprofloxacin hydrochloride demonstrated biocompatibility and antimicrobial activity in vitro.111 Implementing a similar approach, electrospun PVA-silk fibroin nanofibrous mats were developed as bioactive dressings to regulate ECM deposition to augment repair of chronic diabetic wounds.112 Results showed that nanofibrous PVA-silk mats blended with growth factors and LL-37 antimicrobial peptide displayed faster wound healing compared to nonfunctionalized counterparts in rabbit model in vivo.112 In addition, nAg loaded PVA nanogel based WDM has also been developed for wound dressing applications.113 Recently, a composite WDM based on nAg nanogels of polymethacrylic acid (PMA) loaded with AV and Cur coated on PET fabric illustrated fast healing response with antimicrobial activity and minimal scarring in mice in vivo.114 Employing a different strategy, nonwoven PP fabric incorporating bioactive PEG nanogels loaded with bioactive agent and essential oils, including lavender oil, citrus oil, and sandalwood oil, were evaluated as an antimicrobial skin compatible fabric for wound care applications.115 G

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Figure 4. Schematic representing redox respnsive polymeric nanoparticles for codelivery of anticancer drug and siRNA in cancer therapy. Reproduced with permission from ref 131. Copyright 2017 American Chemical Society.

Biosensing. Point of care (POC) diagnostic testing is a rapidly emerging technology that offers accurate real-time monitoring solutions close to the site of patient care.9 It is a cost-effective methodology that assists physicians in making quick informed decisions for effective clinical management of disease.9 The basic requirements for the design of a POC device are that it should be simple to operate, avoid the use of expensive or complicated instrumentation to measure target analytes, utilizes reagents and consumables that are robust in storage and usage, is inexpensive and disposable, and above all should provide valid results in accordance to standard clinical laboratory testing.9 In light of these considerations, novel paper-based microfluidic platforms have been developed to detect biomarkers associated with various disease conditions.116,117 For example, a paper-based colorimetric sensor that exploits the aggregation of positively charged nAg has been developed for ultrasensitive detection of heparin.116 The developed sensor had the ability to detect heparin selectively and in addition, displayed a very low detection limit, spanning between micro- and nanomolar concentrations, thereby demonstrating great capacity for detection of heparin in human blood serum samples.116 Similarly, a paper-based device incorporating gold nanoparticles (nAu) conjugated with graphene oxide was engineered for colorimetric detection of uric acid (UA).117 The designed analytical device had a very low detection limit of 4 ppm and was successfully employed for detection of UA in several human blood serum samples.117 More importantly, the obtained colorimetric readouts were in concurrence with laboratory testing, which underlines its remarkable potential for clinical applications.117 Numerous studies employing nanomaterials, such as nAg, nAu, carbon dots, carbon nanotubes, and quantum dots, have been reported for detection of biomarkers in the diagnosis and monitoring of diseases using cost-effective methodologies. In this context, a nonenzymatic colorimetric detection of glucose based on the inclusion of 4-cyanophenyl boronic acid (CPBA) with β-cyclodextrin stabilized nAu was developed for potential use in the management of diabetes.118 Results showed that the engineered nanoprobes possessed good solubility and exhibited good selectivity for glucose in aqueous media.118 Furthermore, the applicability of this method was validated using human blood serum samples which demonstrated that the developed methodology could detect glucose in the concentration range

between 1−20 mM and hence can be exploited for detection of glucose in biological fluids.118 Applying a similar design, a nonenzymatic carbon dot based approach was employed for detection of glucose in blood serum.119 The emission quenching of carbon dots by CPBA followed by its recovery in glucose medium was utilized for blood glucose sensing.119 Studies showed that this technique had a linear detection range of 1 to 30 mM and hence could serve as a promising platform for glucose monitoring applications.119 The use of biocompatible conducive materials is a growing trend for the fabrication of flexible electronic and optical devices for biomedical applications. In this regard, biodegradable silk proteins have found extensive use as it imparts mechanical robustness, flexibility, optical transparency and is amenable to various facile processing techniques.120 As a case in point, poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) sensors fabricated on flexible biodegradable silk substrate using photolithography technique were developed for use as implantable biosensing materials.121 The fabricated PEDOT:PSS sensors demonstrated high sensitivity toward glucose, dopamine and ascorbic acid in aqueous medium and were found to be electrochemically active, cytocompatible, and stable over a period of 30 days.121,122 Similarly, silk fibroin and nAg composite-based nonvolatile resistive switching memory devices with low operating voltage and high switching ratio were developed for design of eco-friendly printable bioelectronic devices.123 Employing a similar approach, a floating gate memory device based on carbon nanotube-cadmium selenide nanostructures embedded in silk fibroin matrix has been attempted for possible application as bioinspired transparent flash memory devices for printable electronics.124 In another study, indium tin oxide-silk fibroin based memristor devices were fabricated and their resistive switching mechanisms at microscopic scale were investigated in detail for potential biomemristor applications.125

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DRUG DELIVERY SYSTEMS Anticancer drugs. Diverse anticancer drug carrier systems including nano- and microparticles, micelles and liposomes have been developed and evaluated. Aerosol delivery of paclitaxel (Pax) for the treatment of lung cancer and pulmonary metastasis has been evaluated using surface active lipid vesicles.126 These temperature and enzyme responsive vesicles H

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particles exhibit synergistic cytotoxic effect in folate overexpressing cells HeLa and MDA-MB-231. These strategies mainly involved the use of conventional bioactive drug molecules. A nonconventional strategy using single walled carbon nanotube and graphene oxide to potentiate the efficacy of Pax for the treatment of lung cancer has been evaluated.135 Results revealed augmented cell death following the combinatorial treatment of these nanotubes and anticancer drug signifying a synergistic effect. This observed synergism was shown to be dependent on reactive oxygen species (ROS) signifying the novel role of carbon nanotubes to generate ROS as potential cotherapeutics for Pax. Antibiotics and Anti-inflammatory Drugs. A wide range of materials have been employed for the successful delivery of antibiotics, anti-inflammatory drugs, and growth factors. A novel prodrug micellar based approach to deliver ibuprofen was demonstrated using polyethylene glycol-polypropylene fumarate self-assembled micelle nanostructures.136 These ibuprofen loaded micelles exhibited significant anti-inflammatory effects by reducing the prostaglandin E2 levels in rabbit synoviocyte cultures in vitro. A similar prodrug-based approach involving supramolecular interactions between barium and ceramic has been evaluated for improving the stability and delivery of curcumin.137 Studies have also been carried out to mitigate the toxicity of graphene quantum dots for potential use as drug carriers due to their inherent large surface area suitable for π−π interaction-based drug loading.138 The ability of these dots to generate reactive oxygen species responsible for toxicity was inhibited using a pegylation coating to obtain a matrix having size of around 100 nm. These pegylated quantum dots exhibit excellent compatibility coupled with augmented ability of delivering therapeutics. A similar approach was also followed wherein chitosan nanoparticles were sulfonated and studied for the delivery of amphotericin B for the management of Candida glabrata fungemia.139 These nanoparticles assist in delivering the drug to the specified macrophage considerably reducing the potential toxicity of drug. Additionally silk nanoparticles have been investigated for potential therapeutic applications. The antibiotic vancomycin loaded in silk fibroin nanoparticles entrapped in silk scaffolds resulted in continuous, pHdependent, and sustained release patterns over a period of 30 days.140 Radiographic and histopathological analysis performed to evaluate efficacy in treatment confirm reduced bone infection at defect site. Another study using natural silk protein nanoparticles obtained from oak tree Antheraea Pernyi evaluated the antibiotic delivery potential of drugs ibuprofen, and ibuprofen-Na and exhibited charge dependent release profiles.141 In addition, calcium to phosphorus ratios of ceramic nanoparticles was also found to control single and two stage release profiles of doxycycline hyclate drug.142 These nanoparticles possessing needle shaped morphology manifested varying size with tunable degradation profiles. Studies also showed nanosized silicon incorporated HA exhibited morphological changes from rod to spherical and ribbon-like forms with increased silicon content. These microwaves irradiated nanorods also exhibited excellent bioactivity and sustained release of amoxicillin.143 Similarly, a dual local CP delivery system based on CDHA and tricalcium phosphate for the codelivery of tetracycline and ibuprofen aimed at the treatment of periodontitis was developed. In vivo implantation studies on rat demonstrated greater bone formation in the drug-loaded delivery system compared to control at the end of 12 weeks.144

manifest synergistic advantage toward enhanced therapeutic efficacy. Triggered release of Pax was observed in the presence of secretory phospholipase A2 enzyme with maximum release obtained when the triggers were used simultaneously.126 In parallel, a pH responsive nanovesicle demonstrated improved cytosolic drug release enabling higher cytotoxicity in B16F10 murine melanoma cells.127 This aerosol administration significantly improved biodistribution of Pax and higher metatstasis inhibition when compared to paclitaxel administered intravenously. The triggered release of doxorubicin (DOX) loaded into core and shell domains of mesoporous silica nanoparticles and silica based colloidosomes has also been demonstrated. Polymer coated silica nanoparticles revealed spatial control of DOX loading and were responsive to endogenous proteases favoring controlled and localized release of DOX at tumor site in vivo.128 Silica colloidosomes with sub monolayer and close packed multilayer shells, developed using serin microcapsules demonstrate flexible DOX release.129 These DOX-encapsulated colloidosomes can be released in the microenvironment of the cancer cells and show cytotoxic effects on MG-63 cells. Another study involved the use of multiblock copolymeric nanoparticles with disulfide linkages to evaluate folic acid and trastuzumab for breast cancer therapeutics.130 In vivo studies revealed significant antitumor activity with nearly 90% decrease in tumor size when compared to free drug. This increased activity has been attributed to the dual targeting resulting in increased uptake, redox responsive behavior and longer circulation life times. In addition, combination chemotherapy with different modes of action has been actively explored to overcome inherent limitations associated with tumor heterogeneity and achieve better therapeutic outcomes. For instance, a polyethylenimine modified polyplex nanosystem synthesized via atom-transfer free-radical polymerization to deliver DOX and polo-like kinase I siRNA simultaneously has been evaluated for enhanced chemotherapeutic effect (Figure 4). The developed polymeric nanosystem could easily self-assemble into 100 nm sized spherical nanoparticles with enhanced DOX loading coupled with effective siRNA complexation at a polymer to siRNA weight ratio of 15.131 These polyplexes were adept in codelivering both cargoes simultaneously to cells in vitro and demonstrated nearly 30-fold decrease in percent tumor volume in Ehrlich ascites tumor bearing Swiss albino mice compared to control group upon administration in vivo. Likewise, styrenemaleic anhydride based polymeric self-assembling micelles, modified appropriately to overcome systemic barriers for codelivery of nucleic acid and drugs, have been shown to possess optimum loading properties and efficient complexation characteristics.132 These albumin stabilized micelles depict enhanced drug release at pH 5 and in the in the presence of 10 mM glutathione signifying dual stimuli sensitive nature. In vivo results revealed nearly a 15-fold reduction in relative tumor volume indicating efficacy of these micelles in achieving synergistic cytotoxic effects. A delivery system composed of PLGA-chitosan composite particles were dual loaded with Pax followed by topotecan.133 The results obtained indicate that simultaneous treatment of the two anticancer drugs was antagonistic whereas sequential exposure of these two drugs demonstrated synergistic effect on nonsmall cell lung cancer cell line in vitro. Another study along similar lines employed a self-assembled multiblock polymeric system encapsulated with DOX and γFe2O3 superparamagnetic iron oxide nanoparticles.134 In vitro cellular uptake studies of these nanoI

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significantly higher tumor cell death compared to free DOX. Furthermore, biodistribution studies demonstrated augmented accumulation of DOX in tumor tissues in the nanoparticletreated group signifying delivery by passive targeting.155 Metal nanoclusters based on PEGylated lysozyme stabilized silver loaded with phosphatase protein (PTEN) was evaluated for imaging and protein delivery.156 The polyethylene glycol coating permits spherical assembling coupled with retention of both optical functionality of the nanocluster and biological activity of PTEN. The modulation of cellular signaling was evaluated and a dose-dependent reduction in cell proliferation of PTEN expressing MCF7 cell was observed. Co-therapy studies were also carried out on drug resistant U87-MG cells with drug erlotinib and it was observed that the PTEN helped in maneuvering the cells and made them susceptible to erlotinib.156 The research group went on to synthesize a single unit nanotheranostic based on methotrexate templated gold nanocluster which could be the future of nanotheranostics.157 These nanoclusters were bestowed with two functional properties. Primarily, imaging capabilities owing to bright blue luminescence and second, augmented cytotoxicity when compared to the free drug. These nanoclusters had exceptional stability in both PBS and serum and demonstrated augmented cytotoxic effects. It further resulted in higher amount of ROS generation and augmented oxidative stress-induced apoptosismediated cellular death when compared to free drug.157 On similar lines, luminescent phenylboronic acid templated gold nanoclusters was synthesized as a theranostic agent (Figure 5).158 These gold nanoclusters could also serve for diagnostic

A computational study on the binding affinity of various drugs with chitin nanoparticles was evaluated. Molecular docking results derived from the electrostatic and hydrophobic interactions of drug and chitin nanoparticle were successful in predicting encapsulation efficiency in the chitin-based host− guest nanosystems.145 Along similar lines, a biochemical and neurochemical estimation study was carried out to optimize oral delivery of doxycycline hydrochloride using chitosan nanoparticle formulations. The study effectively demonstrated that doxycycline hydrochloride, loaded in Tween 80 coated chitosan nanoparticles, can effectively cross the blood brain barrier for the treatment of psychosis in mice.146 Another study explored the feasibility of vancomycin loaded syringe deliverable gels based on an aldehyde and an antibacterial polymer for treatment of infections in necrotic tissue.147 The hydrogel formulation permitted pH dependent, sustained release of vancomycin over extended time periods. Upon subcutaneous implantation at distal site in rats, around 99.9% of methicillin resistant Staphylococcus aureus was killed thereby convincingly proving its efficacy against drug resistant bacteria. Theranostics. “Theranostics” has evolved to encompass nanoplatforms that include both therapeutic and imaging components to combat various diseases.148 A generic approach to synthesize nanomaterial based capsules containing lanthanides such as gadolinium and terbium to deliver different nanoparticles has been reported.149 These nanoparticle-loaded polymer capsules are effectively internalized by HeLa cells and emit fluorescence demonstrating their potential use in bioimaging and drug delivery.149 Similarly neodymium doped HA nanoparticles employed for the delivery of DOX depict controlled and sustained release profiles along with strong nearinfrared fluorescence emission at 680 nm.150 Fluorescence emission has also been reported by a novel folic acid conjugated Ch-Zn sulfide based quantum dot used for the delivery of 5fluorouracil. In vitro studies using breast cancer cell line MCF-7 reveal bright and stable fluorescence of the quantum dots which could be used for tracking the path of drug enabling targeted imaging of cancer cells.151 Targeted imaging has also been obtained with fibrinogen coated yellow quantum dots for the targeted delivery of paclitaxel toward breast cancer cells imaging studies in vitro.152 Among the various techniques being considered for cancer cell imaging, multimodal imaging is making significant advances leading to better image guided treatment and therapeutics. For example, a multimodal contrast agent based on HA codoped with europium and gadolinium enhanced paramagnetic longitudinal relaxivity suitable for magnetic resonance (MR) imaging coupled with excellent Xray attenuation critical for X-ray contrast imaging. MR contrast enhancement with high transverse relaxivity has been observed in super magnetic iron oxide/polymer hybrid nanoparticles which also demonstrated superior uptake in Hela cells in vitro.153 In addition, photothermal therapy in tune with multimodal imaging, based on plasmon resonant nAu coupled with liposomes demonstrated high efficacy to kill cancer cells in vitro.154 Fluorescent hydroxyquinoline-affixed polyfluorene nanoparticles that demonstrated dual-state optical and fluorescence properties have been investigated for multicolor bioimaging and drug delivery.155 The hydrophobic pockets of these particles were conjugated with DOX and their enhanced anticancer activity was observed in mouse melanoma cancer cells in vitro. In addition, administration of the nanoparticles in a subcutaneous mouse melanoma tumor model demonstrated

Figure 5. Schematic representing gold nanoclusters for cancer cell theranostics. Reproduced with permission from ref 158. Copyright 2018 American Chemical Society.

applications via a rapid “one-step” luminescent assay for mucin detection. The luminescence from the gold nanocluster was used to evaluate imaging and the boron component induced therapeutic effects toward HeLa and HepG2 cancer cells. It further helped in the assessment of phenylboronic acid as an anticancer agent inside cancer cells and multicellular spheroids.158 Additionally nanoprobes based on gold and iron oxide were evaluated for T2 contrast in MR imaging and radiofrequency hyperthermia. In vivo MR imaging on tumorbearing mice after nanoprobe administration showed T2 contrast enhancement leading to tumor tissue damage.159 Apart from the broad areas discussed so far work has also been carried out employing functionalized polymer systems for J

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ability to address these significant issues, which will help provide opportunities for economic growth, better our healthcare system, and usher us into a new era of clinical medicine.

potential brain targeting and efficient gene delivery applications.160,161 Poly ethylene glycol and arginine modified poly ethyl amine polymer showed folate receptor mediated targeting and active accumulation in tumor tissue of mice and capability to diffuse through the vascular endothelium.160 Natural polymer dextran modified by histidine demonstrated around 6-fold higher transfecting capability and could also act as an efficient nucleic acid delivery system.161 Another versatile area which has been explored is surface modification using monolayers of phosphorylcholine for the development of blood-contacting materials. From the protein adsorption studies conducted we observed that either the lipid-modified surfaces adsorb more albumin or the overall protein adsorption is reduced, based upon their orientation resulting in enhanced blood compatibility of these surfaces.162,163

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chandra P. Sharma: 0000-0002-4651-9049 Author Contributions ‡

Both authors contributed equally to this work.

Notes

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The authors declare no competing financial interest.

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CONCLUSION AND FUTURE PERSPECTIVES Biomedical research has attracted tremendous attention in the last few decades and has been instrumental in improving patient compliance and quality of life. Looking ahead, in India, advanced materials including polymeric, ceramic, carbon, supramolecules, peptide and DNA-based biomaterials that can be exploited for drug delivery, scaffolding, soft tissue, photonic, and sensing applications are emerging biomaterial sectors with high research and industrial potential.160 In addition, translation of research outcomes to advanced medical technologies is crucial to realize newer biomedical products. It is envisioned and now understood that convergent technologies from emerging areas of stem cell and tissue engineering, nanotechnology, and bioelectronics/sensors open new avenues that can potentially revolutionize the area of biomedical research. This integrated cross-disciplinary research strategy will be key to the development of novel health-related technologies and will offer solutions to tackle common chronic diseases that currently plague human health. From this perspective, emerging disciplines such as regenerative medicine, nanomedicine, stem cell therapeutics, immunomodulation, miniaturized medical devices, will be principal areas of focus that will be extensively explored by 2035.164 Thus, profound biomaterial innovations coupled with engineering design capabilities would be key to the development of novel and diverse BMDs in the country. However, translation and implementation of these emerging biomedical solutions from bench to clinic will be accompanied by its own regulatory, financial and social hurdles. For instance, BMDs developed through convergent technology platforms present unique challenges to regulators and lawmakers as these products present a paradigm shift to existing regulatory pathways. This uncertainty will lead to a complex productdevelopment path that will inevitably drive up both development and manufacturing costs of newer generation BMDs. In addition, these novel convergence medical products demand a complex business management structure, which when combined with increased costs of regulatory compliance will consequently increase their market entry costs and lower their adoption rate after introduction into the market. This is disadvantageous as increased product costs of newer generation BMDs fall contrary to earlier claims of cost-effectiveness and sustainable healthcare when compared to expensive medical options already available in the market. Another concern is patient compliance as adoption of technologically improved BMDs will be accompanied by its own risks and challenges. Hence success in translation and implementation of emerging biomedical technologies and solutions depends much on our

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ACS Biomaterials Science & Engineering

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DOI: 10.1021/acsbiomaterials.8b00233 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acsbiomaterials.8b00233 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX