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Advanced Drug Delivery Reviews (v.65, #4)

Editorial Board (pp. ii).

Biologically inspired ‘smart’ materials by Wojciech Chrzanowski; Ali Khademhosseini (pp. 403-404).

Bone formation controlled by biologically relevant inorganic ions: Role and controlled delivery from phosphate-based glasses by Nilay J. Lakhkar; In-Ho Lee; Hae-Won Kim; Vehid Salih; Ivan B. Wall; Jonathan C. Knowles (pp. 405-420).

The role of metal ions in the body and particularly in the formation, regulation and maintenance of bone is only just starting to be unravelled. The role of some ions, such as zinc, is more clearly understood due to its central importance in proteins. However, a whole spectrum of other ions is known to affect bone formation but the exact mechanism is unclear as the effects can be complex, multifactorial and also subtle. Furthermore, a significant number of studies utilise single doses in cell culture medium, whereas the continual, sustained release of an ion may initiate and mediate a completely different response. We have reviewed the role of the most significant ions that are known to play a role in bone formation, namely calcium, zinc, strontium, magnesium, boron, titanium and also phosphate anions as well as copper and its role in angiogenesis, an important process interlinked with osteogenesis. This review will also examine how delivery systems may offer an alternative way of providing sustained release of these ions which may effect and potentiate a more appropriate and rapid tissue response.Display Omitted

Keywords: Abbreviations; Akt; Protein Kinase B; ALP; Alkaline phosphatase; ANK; Ankylosis; β; GP; β; glycerophosphate; BMP; Bone morphogenetic protein; CFU; Colony forming units; DC; Dendritic cell; DMEM; Dulbecco's Modified Eagle Medium; ECM; Extracellular matrix; ER; Endoplasmic reticulum; ERK; Extracellular signal-related kinase; FPPS; Farnesyl pyrophosphate synthetase; IL; Interleukin; IP3R; 1,4,5-Triphosphate receptor; LPS; lipopolysaccharide; MAS-NMR; Magic angle spinning-nuclear magnetic resonance; MT; Metallothionein; NFAT2; Nuclear factor of activated T-cells; NO; Nitric oxide; NTPPPH; Nucleoside triphosphate pyrophosphohydrolase; OPN; Osteopontin; PC-1; Plasma cell membrane glycoprotein-1; Pi; Orthophosphate; PI3K; Phosphatidylinositol 3-kinase; PPi; Pyrophosphate; PET; Positron emission tomography; RANKL; Receptor activator of nuclear factor kappa-B ligand; RyR2; Ryanodine receptor 2; Runx2; Runt-related transcription factor; SaOS-2; Human osteosarcoma cell line; SBF; Simulated body fluid; TGF; Transforming growth factor; TNF; Tumour necrosis factor; TRAP; Tartrate resistant acid phosphatase; VEGF; Vascular endothelial growth factorBone; Controlled release; Ions; Calcium; Phosphate; Zinc; Strontium; Magnesium; Titanium; Copper; Boron

Tropoelastin — A multifaceted naturally smart material by Suzanne M. Mithieux; Steven G. Wise; Anthony S. Weiss (pp. 421-428).

Tropoelastin dominates the physical performance of human elastic tissue as it is assembled to make elastin. Tropoelastin is increasingly appreciated as a protein monomer with a defined solution shape comprising modular, bridged regions that specialize in elasticity and cell attachment, which collectively participate in macromolecular assembly. This modular, multifaceted molecule is being exploited to enhance the physical performance and biological presentation of engineered constructs to augment and repair human tissues. These tissues include skin and vasculature, and emphasize how growing knowledge of tropoelastin can be powerfully adapted to add value to pre-existing devices like stents and novel, multi-featured biological implants.Display Omitted

Keywords: Abbreviations; BS3; bis-sulfosuccinimidyl suberate; DSS; disuccinimidyl suberate; EBP; elastin binding protein; ECM; extracellular matrix; GA; glutaraldehyde; HAEC; human aortic endothelial cells; HASMC; human aortic smooth muscle cells; HCAEC; human coronary artery endothelial cells; HCASMC; human coronary artery smooth muscle cells; HDF; human dermal fibroblast; HMDI; hexamethylene diisocyanate; HMVEC; human microvascular endothelial cells; HUVEC; human umbilical vein endothelial cells; IMA; internal mammary artery; kDa; kilodaltons; kPa; kilopascals; PAC; plasma activated coating; PCL; polycaprolactone; PIII; Plasma immersion ion implantation; PPII; polyproline type II; PTFE; polytetrafluoroethylene; R515A; Tropoelastin with an Alanine substitution for Arginine at position 515Tropoelastin; Elastin; Elasticity; Extracellular matrix; Tissue; Tissue engineering; Regenerative medicine

Collagen — Emerging collagen based therapies hit the patient by Ensanya A. Abou Neel; Laurent Bozec; Jonathan C. Knowles; Omaer Syed; Vivek Mudera; Richard Day; Jung Keun Hyun (pp. 429-456).

The choice of biomaterials available for regenerative medicine continues to grow rapidly, with new materials often claiming advantages over the short-comings of those already in existence. Going back to nature, collagen is one of the most abundant proteins in mammals and its role is essential to our way of life. It can therefore be obtained from many sources including porcine, bovine, equine or human and offer a great promise as a biomimetic scaffold for regenerative medicine. Using naturally derived collagen, extracellular matrices (ECMs), as surgical materials have become established practice for a number of years. For clinical use the goal has been to preserve as much of the composition and structure of the ECM as possible without adverse effects to the recipient. This review will therefore cover in-depth both naturally and synthetically produced collagen matrices. Furthermore the production of more sophisticated three dimensional collagen scaffolds that provide cues at nano-, micro‐ and meso-scale for molecules, cells, proteins and bulk fluids by inducing fibrils alignments, embossing and layered configuration through the application of plastic compression technology will be discussed in details. This review will also shed light on both naturally and synthetically derived collagen products that have been available in the market for several purposes including neural repair, as cosmetic for the treatment of dermatologic defects, haemostatic agents, mucosal wound dressing and guided bone regeneration membrane. There are other several potential applications of collagen still under investigations and they are also covered in this review.Display Omitted

Keywords: Abbreviations; ANG; autologous nerve graft; BDNF; brain-derived neurotrophic factor; BATs; bioartificial tendons; b-FGF; basic fibroblast growth factor; CEA; cultured epidermal autograft; CNC; computerised numerical control; CMAP; compound muscle action potential; DMEM; Dulbecco's modified Eagles medium; DNA; deoxyribonucleic acid; ECM; extracellular matrix; FACITs; fibril-associated collagens with interrupted triple helices; GAG; glycosaminoglycan; Gal; galactosyl-a-1,3-galactose; GBR; guided bone regeneration; GTR; guided tissue regeneration; Gly-X-Y; glycine–proline–hydroxyproline; IgM; Immunoglobulin M; LESC; limbal epithelium stem cells; LOCS; linear-ordered collagen scaffolds; MMPs; matrix metalloproteinases; MRI; magnetic resonance imaging; NTIRE; non-thermal irreversible electroporation; PC; plastic compression; OA; osteoarthritis; PGA; polyglycolic acid; PHEMA-MMA; poly(2-hydroxyethyl methacrylate-co-methyl methacrylate); PLC; poly; dl; -lactide-ε-caprolactone; PTFE; polytetrafluroethylene; RH; relative humidity; SDS; sodium dodecylsulfate; SIS; small intestine submucosa; NaOH; sodium hydroxide; TE; tissue engineering; TGF; transforming growth factor; Th; T helper cell; UBM; urinary bladder matrix; VEGF; vascular endothelial growth factorProtein-based materials; Collagen; Natural; versus; synthetic collagen biomaterials; Plastic compressed collagen; Clinical use; Collagen nano-particles

Silk fibroin biomaterials for tissue regenerations by Banani Kundu; Rangam Rajkhowa; Subhas C. Kundu; Xungai Wang (pp. 457-470).

Regeneration of tissues using cells, scaffolds and appropriate growth factors is a key approach in the treatments of tissue or organ failure. Silk protein fibroin can be effectively used as a scaffolding material in these treatments. Silk fibers are obtained from diverse sources such as spiders, silkworms, scorpions, mites and flies. Among them, silk of silkworms is a good source for the development of biomedical device. It possesses good biocompatibility, suitable mechanical properties and is produced in bulk in the textile sector. The unique combination of elasticity and strength along with mammalian cell compatibility makes silk fibroin an attractive material for tissue engineering. The present article discusses the processing of silk fibroin into different forms of biomaterials followed by their uses in regeneration of different tissues. Applications of silk for engineering of bone, vascular, neural, skin, cartilage, ligaments, tendons, cardiac, ocular, and bladder tissues are discussed. The advantages and limitations of silk systems as scaffolding materials in the context of biocompatibility, biodegradability and tissue specific requirements are also critically reviewed.Display Omitted

Keywords: Silk; Fibroin; Biomaterials; Scaffolds; Tissue regeneration

Naturally and synthetic smart composite biomaterials for tissue regeneration by Perez Román A. Pérez; Jong-Eun Won; Jonathan C. Knowles; Hae-Won Kim (pp. 471-496).

The development of smart biomaterials for tissue regeneration has become the focus of intense research interest. More opportunities are available by the composite approach of combining the biomaterials in the form of biopolymers and/or bioceramics either synthetic or natural. Strategies to provide smart capabilities to the composite biomaterials primarily seek to achieve matrices that are instructive/inductive to cells, or that stimulate/trigger target cell responses that are crucial in the tissue regeneration processes. Here, we review in-depth, recent developments concerning smart composite biomaterials available for delivery systems of biofactors and cells and scaffolding matrices in tissue engineering. Smart composite designs are possible by modulating the bulk and surface properties that mimic the native tissues, either in chemical (extracellular matrix molecules) or in physical properties (e.g. stiffness), or by introducing external therapeutic molecules (drugs, proteins and genes) within the structure in a way that allows sustainable and controllable delivery, even time-dependent and sequential delivery of multiple biofactors. Responsiveness to internal or external stimuli, including pH, temperature, ionic strength, and magnetism, is another promising means to improve the multifunctionality in smart scaffolds with on-demand delivery potential. These approaches will provide the next-generation platforms for designing three-dimensional matrices and delivery systems for tissue regenerative applications.Display Omitted

Keywords: Abbreviations; BDNF; brain derived neurotrophic factor; bFGF; basic fibroblast growth factor; BMP; bone morphogenetic protein; BSA; bovine serum albumin; CaP; calcium phosphate; CCBD; central cell binding domain; CNT; carbon nanotube; CPC; calcium phosphate cement; DGEA; Asp–Gly–Glu–Ala (amino acid sequence); DNA; deoxyribonucleic acid; DOX; doxorubicin; ECM; extracellular matrix; EGF; epidermal growth factor; FN; fibronectin; GDNF; glial cell line-derived neurotrophic factor; GAG; glycosaminoglycan; G-CSF; granulocyte colony stimulating factor; GF; growth factor; GFP; green fluorescent protein; HA; hydroxyapatite; HGF; hepatocyte growth factor; HEMA; 2-hydroxyethyl methacrylate; HPMC; hydroxypropylmethylcellulose; HUVEC; human umbilical vein endothelial cell; IGF; insulin-like growth factor; IKVAV; Ile–Lys–Val–Ala–Val (amino acid sequence); IPTS; (3-isocyanatopropyl)triethoxysilane; MSC; mesenchymal stem cells; MSN; mesoporous silica nanoparticles; NGF; nerve growth factor; MNP; magnetic nanoparticle; NT3; neutrophin-3; OCN; osteocalcin; OPN; osteopontin; PA; peptide amphiphile; PAA; poly(acryl amide); PCL; poly(ε-caprolactone); PDGF; platelet derived growth factor; PDMS; polydimethylsiloxane; PEG; poly(ehylene glycol); PEI; polyethylenimine; PEO; poly(ethylene oxide); PET; poly(ethylene terephthalate); PGMMA; poly(glycerolmonomethacrylate); PHPMA; poly[n-(2-hydroxypropyl)methacrylamide]; PHSRN; Pro–His–Ser–Arg–Asn (amino acid sequence); PLA; poly(lactic acid); PLGA; poly(lactic-co-glycolic acid); PLLA; poly(; l; -lactic acid); PMMA; poly(methyl methacrylate); pNIPAAm; poly(N-isopropyl acrylamide); PPG; poly(propylene glycol); PPO; poly(propylene oxide); PTX; paclitaxel; PVA; poly(vinyl alcohol); RGD; Arg–Gly–Asp (amino acid sequence); RNA; ribonucleic acid; siRNA; small interfering RNA; TCP; tricalcium phosphate; TGF; transforming growth factor; VEGF; vascular endothelial growth factorSmart biomaterials; Composites; Tissue regeneration; Biomimetic approach; Biofactors delivery; Multifunctional; Stimuli-responsive

Remote and local control of stimuli responsive materials for therapeutic applications by Alexander Chan; Rowan P. Orme; Rosemary A. Fricker; Paul Roach (pp. 497-514).

Materials offering the ability to change their characteristics in response to presented stimuli have demonstrated application in the biomedical arena, allowing control over drug delivery, protein adsorption and cell attachment to materials. Many of these smart systems are reversible, giving rise to finer control over material properties and biological interaction, useful for various therapeutic treatment strategies. Many smart materials intended for biological interaction are based around pH or thermo‐responsive materials, although the use of magnetic materials, particularly in neural regeneration, has increased over the past decade. This review draws together a background of literature describing the design principles and mechanisms of smart materials. Discussion centres on recent literature regarding pH-, thermo-, magnetic and dual responsive materials, and their current applications for the treatment of neural tissue.Display Omitted

Keywords: Abbreviations; RGD; arginine–glycine–aspartate; AEH; arterial embolization hyperthermia; ATRP; atom transfer radical polymerisation; BMP; bone morphogenetic protein; BA; butyl acrylate; CIPAM; carboxy isopropylacrylamide; DIH; direct injection hyperthermia; DRG; dorsal root ganglion; DOX; doxorubicin; EVAc; ethylene vinyl acetate; ECM; extracellular matrix; bFGF; basic fibroblast growth factor; GI; gastrointestinal; hMSC; human mesenchymal stem cells; HUVECs; human umbilical vein endothelial cells; HPG; hyperbranched poly(glycidol); IFN-γ; interferon-gamma; IH; intracellular hyperthermia; LCST; lower critical solution temperature; MRI; magnetic resonance imaging; MMH; magnetically mediated hyperthermia; MAA; methacrylic acid; SPION; superparamagnetic iron oxide nano particle; NP; nano particle; NGF; nerve growth factor; NSCs; neural stem cells; poly(MEO; ₂; MA‐co‐OEGMA); poly(methoxyethoxyethylmethacrylate-co-oligoethyleneglycolmethacrylate); PVA; poly vinylalcohol; PSS; poly(4-styrene sulfonate); PAA; poly(acrylic acid); PAH; poly(allylamine hydrochloride); PCLA; poly(ε‐caprolactone-co-lactide); PEG; poly(ethylene glycol); PMMA; poly(methyl methacrylate); PDMAEMA; poly(N,N-dimethylaminoethyl methacrylate); pNIPAM; poly(; N; -isopropylacrylamide); pNIPAM-CS; poly(N-isopropylacrylamide)-chitosan; p(NiPAM-co-AAc); poly(N-isopropylacrylamide-co-acrylic acid); PPO; poly(propylene-oxide); IPA-PSI; poly[α/β-(; dl; -asparate isopropylamide)-co-(succinimide)]; PDL; poly-; d; -lysine; PEM; polyelectrolyte multilayers; PEO; polyethyle oxide; PCL; polycaprolactone; PGA; polyglycolic acid; PLA; polylactic acid; PM; polymeric micelle; SAM; self assembled monolayerSmart; Responsive; pH; Thermal; Magnetic; Neural regeneration/ therapy

Shaping tissue with shape memory materials by W.M. Huang; C.L. Song; Y.Q. Fu; C.C. Wang; Y. Zhao; H. Purnawali; H.B. Lu; C. Tang; Z. Ding; J.L. Zhang (pp. 515-535).

After being severely and quasi-plastically deformed, shape memory materials are able to return to their original shape at the presence of the right stimulus. After a brief presentation about the fundamentals, including various shape memory effects, working mechanisms, and typical shape memory materials for biomedical applications, we summarize some major applications in shaping tissue with shape memory materials. The focus is on some most recent development. Outlook is also discussed at the end of this paper.Display Omitted

Keywords: Shape memory material; Shape recovery; Tissue; Stimulus; Shape memory alloy; Shape memory polymer; Shape memory hybrid

Nanotopography-guided tissue engineering and regenerative medicine by Hong Nam Kim; Alex Jiao; Nathaniel S. Hwang; Min Sung Kim; Do Hyun Kang; Deok-Ho Kim; Kahp-Yang Suh (pp. 536-558).

Human tissues are intricate ensembles of multiple cell types embedded in complex and well-defined structures of the extracellular matrix (ECM). The organization of ECM is frequently hierarchical from nano to macro, with many proteins forming large scale structures with feature sizes up to several hundred microns. Inspired from these natural designs of ECM, nanotopography-guided approaches have been increasingly investigated for the last several decades. Results demonstrate that the nanotopography itself can activate tissue-specific function in vitro as well as promote tissue regeneration in vivo upon transplantation. In this review, we provide an extensive analysis of recent efforts to mimic functional nanostructures in vitro for improved tissue engineering and regeneration of injured and damaged tissues. We first characterize the role of various nanostructures in human tissues with respect to each tissue-specific function. Then, we describe various fabrication methods in terms of patterning principles and material characteristics. Finally, we summarize the applications of nanotopography to various tissues, which are classified into four types depending on their functions: protective, mechano-sensitive, electro-active, and shear stress-sensitive tissues. Some limitations and future challenges are briefly discussed at the end.We summarize the applications of nanotopography to various tissues, which are classified into four types depending on their functions: protective, mechano-sensitive, electro-active, and shear stress-sensitive tissues.Display Omitted

Keywords: Nanotopography; Tissue engineering; Regenerative medicine; Biomaterials; Cell–material interface

Controlled delivery for neuro-bionic devices by Zhilian Yue; Simon E. Moulton; Mark Cook; Stephen O'Leary; Gordon G. Wallace (pp. 559-569).

Implantable electrodes interface with the human body for a range of therapeutic as well as diagnostic applications. Here we provide an overview of controlled delivery strategies used in neuro-bionics. Controlled delivery of bioactive molecules has been used to minimise reactive cellular and tissue responses and/or promote nerve preservation and neurite outgrowth toward the implanted electrode. These effects are integral to establishing a chronically stable and effective electrode-neural communication. Drug-eluting bioactive coatings, organic conductive polymers, or integrated microfabricated drug delivery channels are strategies commonly used.Display Omitted

Keywords: Neuro-bionics; Controlled release; Organic conductive polymers; Drug-eluting coatings; Nerve preservation; Electrode-neural interfacing; Foreign body response

Shining light on materials — A self-sterilising revolution by Sacha Noimark; Charles W. Dunnill; Ivan P. Parkin (pp. 570-580).

This review focuses on the development of light activated antimicrobial surfaces. These surfaces kill microbes by the action of light and have potential applications in domestic and healthcare settings. The inspiration for the new self-cleaning surfaces originates from photodynamic therapy where light is used to locate and destroy tumours. The first generation photosensitiser molecules, based on a porphyrin ring structure, could be considered as bioinspired and chemically related to chlorophyll. The review looks at developments of both soft polymeric surfaces with either surface bound or impregnated photosensitiser molecules; and hard inorganic surfaces such as modified titanium dioxide. The bacterial kill mechanisms are looked into with both surface types showing primary microbial kill through a radical induced pathway. The hard inorganic surfaces also show low bacterial adherence by means of a light activated photo-wetting of the surfaces meaning that they are “Easy Clean” and wash off microbes uniformly.This review explores the recent advances in light activated functional materials for applications in a healthcare environment, looking specifically at the antimicrobial functionality of both hard and soft surfaces.Display Omitted

Keywords: Antimicrobial surfaces; Titania; TiO; ₂; Doped TiO; ₂; Doped titania; Functional materials and functional surfaces; Photodynamic therapy; Photosensitiser dyes; Photocatalysis of microbes

How smart do biomaterials need to be? A translational science and clinical point of view by Boris Michael Holzapfel; Johannes Christian Reichert; Jan-Thorsten Schantz; Uwe Gbureck; Lars Rackwitz; Noth Ulrich Nöth; Franz Jakob; Maximilian Rudert; Jürgen Groll; Dietmar Werner Hutmacher (pp. 581-603).

Over the last 4 decades innovations in biomaterials and medical technology have had a sustainable impact on the development of biopolymers, titanium/stainless steel and ceramics utilized in medical devices and implants. This progress was primarily driven by issues of biocompatibility and demands for enhanced mechanical performance of permanent and non-permanent implants as well as medical devices and artificial organs. In the 21st century, the biomaterials community aims to develop advanced medical devices and implants, to establish techniques to meet these requirements, and to facilitate the treatment of older as well as younger patient cohorts. The major advances in the last 10years from a cellular and molecular knowledge point of view provided the scientific foundation for the development of third-generation biomaterials. With the introduction of new concepts in molecular biology in the 2000s and specifically advances in genomics and proteomics, a differentiated understanding of biocompatibility slowly evolved. These cell biological discoveries significantly affected the way of biomaterials design and use. At the same time both clinical demands and patient expectations continued to grow. Therefore, the development of cutting-edge treatment strategies that alleviate or at least delay the need of implants could open up new vistas. This represents the main challenge for the biomaterials community in the 21st century. As a result, the present decade has seen the emergence of the fourth generation of biomaterials, the so-called smart or biomimetic materials. A key challenge in designing smart biomaterials is to capture the degree of complexity needed to mimic the extracellular matrix (ECM) of natural tissue. We are still a long way from recreating the molecular architecture of the ECM one to one and the dynamic mechanisms by which information is revealed in the ECM proteins in response to challenges within the host environment. This special issue on smart biomaterials lists a large number of excellent review articles which core is to present and discuss the basic sciences on the topic of smart biomaterials. On the other hand, the purpose of our review is to assess state of the art and future perspectives of the so called “smart biomaterials” from a translational science and specifically clinical point of view. Our aim is to filter out and discuss which biomedical advances and innovations help us to achieve the objective to translate smart biomaterials from bench to bedside. The authors predict that analyzing the field of smart biomaterials from a clinical point of view, looking back 50years from now, it will show that this is our heritage in the 21st century.Display Omitted

Keywords: Smart biomaterials; Clinical translation; Medical devices and implants; Tissue engineering; Orthopedic surgery; Plastic surgery–extracellular matrix

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Advanced Drug Delivery Reviews (v.65, #4)