ozdil2014

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ReviewReceived: 20 May 2014 Revised: 24 July 2014 Accepted article published: 4 August 2014 Published online in Wiley Online Library: 3 September 2014

(wileyonlinelibrary.com) DOI 10.1002/jctb.4505

Polymers for medical and tissue engineeringapplicationsDeniz Ozdila and Halil Murat Aydina,b*

Abstract

Recent decades have seen great advancements in medical research into materials, both natural and synthetic, that facilitate therepair and regeneration of compromised tissues through the delivery and support of cells and/or biomolecules. Biocompatiblepolymeric materials have become the most heavily investigated materials used for such purposes. Naturally-occurring andsynthetic polymers, including their various composites and blends, have been successful in a range of medical applications,proving to be particularly suitable for tissue engineering (TE) approaches. The increasing advances in polymeric biomaterialresearch combined with the developments in manufacturing techniques have expanded capabilities in tissue engineeringand other medical applications of these materials. This review will present an overview of the major classes of polymericbiomaterials, highlight their key properties, advantages, limitations and discuss their applications.© 2014 Society of Chemical Industry

Keywords: polymers; tissues and organs; scaffolds; tissue engineering

INTRODUCTIONRegenerative medicine has seen great advancements over thepast decade with progress in polymer science offering new materi-als and strategies for the fields of tissue engineering, drug delivery,and cosmetic surgery. For tissue engineering research, the primaryfocus has been on developing substitutes for the natural extra-cellular matrix (ECM) – scaffolds capable of acting as temporarythree-dimensional support structures that promote and guide cor-rect tissue pattern formation. Polymers, both naturally-occurringand synthetic, have become the natural choice of biomaterialfor such applications for a number of reasons including theiravailability as a resource and ability to be easily reproduced,their versatility in the range of applications for which they can beadapted, their generally tuneable properties for function-specificuse and the biodegradable nature of most of them. As poly-meric scaffolds are generally subjected to in vivo conditionsthey are also generally required to possess good cell adhesive-ness, promote cell–biomaterial interactions, exhibit structuraland mechanical integrity, and have a microstructure suitablefor tissue integration and the exchange of factors critical to cellsurvival.

Scaffold design parameters and manufacturing methods formulti-faceted polymer systems ultimately rely on the funda-mental chemical nature of the polymer. For example, whilecollagen is degradable and highly suitable as temporary scaffold-ing material for repair at defect sites, the mechanical strengthand non-degradability of polyurethanes are sought for loadbearing applications. Polymers used as biomaterials in biomed-ical applications can be separated into two broad categories:naturally-occurring polymers and synthetic polymers. As biomed-ical polymers are usually combined with other materials formaximized performance and targeted tissue response, thisreview will discuss each type of polymer separately under theaforementioned categories.

NATURALLY-OCCURRING POLYMERSThe first polymers to be used in biomedical applications,naturally-occurring polymers,1 far out-date the use of syn-thetic polymers which first appeared around the 1960s.Frequently-utilized, naturally-occurring polymers can be dividedinto the following three groups: proteins (e.g. silk, collagen, soy,fibrin gels), polysaccharides (e.g. chitin/chitosan, alginate andhyaluronic acid derivatives) and polynucleotides (e.g. DNA andRNA).2 The main advantage of natural polymers is their highdegree of scaffold–tissue compatibility due to the positive bio-logical recognition of their chemical make-up. However, the use ofthese polymers also carries the potential for inciting an immuneresponse due to any impurities in the material gained duringprocessing. Clinical applications require the use of medical gradematerials and, in any instances where immunogenic fragmentsare detected within the material, it is imperative that they areremoved.

Hyaluronic acidA ubiquitous proteoglycan, and one that is often incorporatedinto tissue regenerative scaffolds, is the linear, anionic polymer,hyaluronic acid. This co-polymer of D-glucuronic acid and N-acetyl-D-glucosamine can be found in several body tissues includ-ing connective, epithelial and neural tissue and synovial fluid.3

∗ Correspondence to: Halil Murat Aydin, Environmental Engineering Departmentand Bioengineering Division, Hacettepe University, 06800, Ankara, Turkey.E-mail: [email protected]

a BMT Calsis Co., Hacettepe University Technopolis, 06800, Beytepe, Ankara,Turkey

b Environmental Engineering Department & Bioengineering Division and Centerfor Bioengineering, Hacettepe University, 06800, Ankara, Turkey

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Hyaluronic acid not only has a key role in ensuring joint lubricationbut is also known to promote cell motility and proliferation whichare properties critical for tissue regeneration. These features,alongside the enzymatic degradability, bioresorbability and theability to add further functionality via its side chains has led to thedevelopment of hyaluronic-based scaffolds of all forms includinghydrogels for wound healing applications,4 sponges for cartilagerepair,5 and meshes for bone tissue engineering.6 It is perhaps themore specific features of hyaluronic acid such as its ability to orga-nize and retain aggrecan and sulphated glycosaminoglycans,7

its ability to adhere chondrocytes through cell surface receptorswhich then leads to the production of signals for cell migration,proliferation and differentiation,8,9 and its ability to stimulate pro-teoglycan synthesis10,11 that has made it so popular in cartilagetissue.

Hyaluronic acid is also known to take part in the stimulation ofa local inflammatory response which is particularly useful for theconduction of local tissue repair and remodelling.12 In addition,the angiogenic effects13 of hyaluronic acid have been documentedand add further appeal to the natural biomaterial as local angio-genesis is considered critical for tissue formation and survival. Inrecent years chemical modifications to hyaluronic acid have beenexplored to chemically enhance its physical qualities, rheologicalqualities and tissue–material interactive qualities. Such upgradeswill continue to inspire future research into the use hyaluronic acidin tissue engineering applications.

CollagenCollagens are extra cellular matrix proteins. Type I collagen, afibrillar, rod-shaped molecule,14 is the most abundant of the 27different types of collagen. Type I collagen can be purified froma number of tissues including tendon, ligament, bone, skin andcornea via relatively simple biochemical processing methods.15

The high content of collagen Type I in the extracellular matrix hasbeen a key reason why it has become one of the most investigatedproteins for use in medical applications.16 As it normally providesthe structural framework and tensile strength in body tissues17 itis considered an excellent biological resource for the constructionof tissue engineering scaffolds.

The mechanical performance of collagen relies heavily onthe fundamental crystalline assembly of the protein which hasa helical quaternary structure.18 At the nanoscale, the helicalself-assembly of tropocollagen subunits form the collagen fib-rils that are cross-linked at the microscale to give the ECM andtissues its tensile strength. The interactions of these fibrils withother proteins and extracellular matrix components also play arole in defining the engineered tissue matrix. At this level, fibrildiameter, length, density and orientation can all be modified toenhance the biological and mechanical activity of the scaffold.The covalent bonding between fibrils to form larger fibrils or fibrebundles can be attained through various fabrication methods,including electro-spinning modules and moulding. The appli-cation of mechanical stimulation such as tensile strain19 andcyclic circumferential strain20,21 on collagen Type I-based scaffoldshave proven to assist with the control of collagen deposition bythe recruited cells and therefore serves as a tool for directing thestructural formation of the scaffold.

Collagen carries the advantage of having simulative chemicalcharacteristics, such as integrin receptors, required for adequatecell attachment and proper tissue formation.22,23 Furthermore, thetypes of cells that are attracted to and attach to this biomaterialnot only secrete specific enzymes that degrade the collagen

without creating cytotoxic degradation products, but they arealso the chief synthesizers of new collagen that is deposited in tothe extracellular space. This gives collagen scaffolds behaviouralcharacteristics that are ideal and capable of closely following thebone remodelling process that governs bone tissue engineeringapplications. Collagen can be forged to exhibit the physical andmorphological features required for local connective tissue regen-eration, combined with other materials (for example 𝛽-tricalciumphosphate for bone tissue engineering) to form composites andprepared in many different physical forms (beads, membranes,shaped objects, etc.).24,25 Currently, the main issue with collagenuse from a regulatory perspective is the challenges that are asso-ciated with ensuring the safety with using such animal-derivedmaterials (in particular the risk of transmitting prions and BSE).

Co-polymerization capabilities with other biomaterials raiseeven more options for customizing scaffold properties.

Chitin/ChitosanThe second most abundant polymer in nature is chitosan, a lin-ear cationic polysaccharide that is attained from the deacety-lation of chitin (a linear polysaccharide built from 𝛽-1,4 linkedN-acetylglucosamine units). Owing to the insolubility of chitin incommon solvents and the difficulties this poses for processing,deacetylation is necessitated and chitosan becomes the usableproduct. Chitosan is a promising degradable polymer that is oneof the only two non-human origin natural polymers (along withalginic acid) used in biomedical engineering. Its base unit, chitin,has characteristics, such as wound healing capacity,26 that are par-ticularly favourable in tissue engineering cases. The crystallinityand molecular weight of the chitosan polymer depends on thedegree of deacetylation.27 The degradation of chitosan is alsoprimarily influenced by the degree of acetylation.28 The alterna-tive method for controlling degradation profiles is by altering theside-groups of the polymer such that extensive hydrogen bond-ing is prevented via the attachment of bulky side groups.29 In vitrodegradation of chitosan is performed by several enzymes includ-ing chitosanase, lysozyme and papain30 with lysozyme being thephysiologically relevant enzyme for in vivo degradation.

The poor mechanical strength of chitosan and its high degreeof hydrophilicity has traditionally been resolved by cross-linkingit to other polymers such as collagen,31,32 poly(lactic acid) (PLA),33

poly(lactic-co-glycolic acid) (PLGA),33,34 polyethylene glycol PEG35

and alginate.36 The various cross-linked forms of chitosan withother polymers include semi- or full-interpenetrating polymernetworks, chitosan–chitosan networks and hybrid polymernetworks.37,38 The structural stability of chitosan-based scaffoldscan thus be varied through these cross-links.

This cationic polymer is able to form electrostatic interactionswith negatively charged cell surfaces and, depending on its con-figuration, it can also display great hydrophilicity and cell prolifer-ation effects.39,40 The ability of this bioactive polymer to interactwith glycosaminoglycans (GAGs) in particular give scaffolds basedon chitosan a direct influence on the modulation of cytokinesand growth factors41 and thus local tissue regeneration activities.Furthermore, chitosan–DNA complexes have also been exploredas a means of facilitating the regeneration process via scaffoldswith amplified bioactivity at the molecular level.42

The biodegradability, biocompatibility, bio-adhesiveness, andnon-toxicity of chitosan41,43 account for the popularity of thisbiomaterial in medicine. This is topped by the possibility ofprocessing chitosan and chitosan-composites into numerous

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shapes; membranes, sponges, fibres, microspheres and hydro-gels. Some recent research into chitosan-based scaffolds areaimed at further improving surface characteristics of scaffolds forhard tissue regeneration,44 exploring its anti-bacterial qualitieswhen combined with other polymers and anti-bacterial agents,45

increasing stability of chitosan-based cartilage repair scaffoldsby co-polymerization with other natural polymers,46 and intro-ducing chitosan microspheres embedded in calcium sulphate aspoint-of-care drug delivery systems.47 Bovine derived collagen,much like the innovative uptake of fungi-derived chitosan, can beused as an example by which solutions for the abovementionedissues can be found, paving the way for the safe and effectivefuture use of this material.

AlginateThe other non-human derived natural polymer used to fab-ricate tissue engineering scaffolds is the linear copolymer of𝛽-D-manuronic acid and 𝛼-L-glucuronic acid linked by a 1–4 gly-cosidic bond, alginate. Commonly sourced from the cell wall ofbrown algae, extraction of the polysaccharide is through the useof a basic solution followed by acidic precipitation. The molecularweight of the polysaccharide can reach up to 500 kDa.

The simplicity of creating alginate hydrogels with the poly-mer undergoing spontaneous gelation in the presence of diva-lent cations and carboxylate side groups makes it an attractiveand promising biomaterial with tissue engineering applicationpotential. Traditionally, along with drug delivery and cell deliveryscaffolds,48 alginate has also been used in wound dressings.

Most research and development in hydrogel based systemshave been centred on composite constructs that incorporatedifferent materials such as collagen49,50 PLGA,51,52 Poly-L-lysine(PLL),53,54 PCL,55 polyethers,56 and chitosan,57,58 mainly for supportof alginate’s mechanical weakness. Scaffold designs are as variedas the types of body tissues that are aimed to be restored fromgels,59,60,50 porous networks,61,62 and sponges63 to films64 andmicrospheres.65,49,54,53 Along with its design flexibility is the abilityto transform the responsiveness of alginate biomaterials towardpH and cell adhesion through alterations to its carboxylate acidside group.66,67

Among these advantages, however, stand alginate’s natural poorcell adhesion and poor in vivo degradation performance. Thisnecessitates either the gamma irradiation or periodates oxidationof alginate biomaterials. Several types of alginate-based scaffoldshave been used in tissue regeneration attempts of different bodytissues including bone and cartilage,61,59,63,60 nerve,54 and connec-tive tissue.50

FibrinFibrinogen, the building block of fibrin, is a large (340 kD) glycopro-tein that has three pairs of polypeptide chains, namely A𝛼, B𝛽 , and𝛾 which are bound by disulphide bridges. A unique polymerisa-tion process involving thrombin and activated factor XIII convertsfibrinogen into fibrin and forms a fibrin network. This polypeptideis commonly known for its physiological role as a haemostaticplug in tissue injuries. The options for cross-linking are one wayin which diverse microstructural and mechanical features of fibrinnetworks can be achieved. In addition, autologous scaffolds canbe manufactured by using fibrin made from a patient’s own blood.

Injectable fibrin hydrogels are the most frequently utilized formsof the polypeptide as tissue regeneration support biomaterial68

Fibrin can adhere cells both directly via integrin receptors and

indirectly by binding extracellular matrix proteins in the blood.69,70

The polymer also binds growth factors that further promote cellproliferation and differentiation.71 Furthermore, the angiogeniceffects of fibrin-based materials have also been established.72 Thisbioactivity gives fibrin significant appeal and use in medicine assealants or heamostatic agents, which are perhaps the more com-monly known applications of the biopolymer. However, fibrin hasalso shown success as a biomaterial with tissue engineering appli-cability. Orthopaedic, cardiovascular and skin tissue engineeringare key examples of areas with fibrin-based scaffold use.73 – 78

The main impediment to the use of fibrin as scaffolding mate-rial is its morphological deconfiguration (shrinkage) and rapiddegradation in physiological conditions.73,74 Fibrin-only cellcarriers79 are weak mechanically and thus require combinationswith strength enhancers, e.g. hyaluronic acid,80 PLGA81 andPCL/polyurethane.82 Like all successful 3D scaffolds for tissueengineering, fibrin-based scaffolds can exhibit interconnectedpores that allow cell infiltration, the exchange of nutrients andwastes and that support vascularization.83 Fibrinogen concen-tration is the fundamental determining factor of pore structurewhere a low concentration creates appropriately dense matricesthat can mediate the aforementioned points critical for scaffoldperformance.84 – 86

AlbuminAlbumin, a protein that contributes 50% to the total mass ofblood plasma has been investigated for use in drug deliveryapplications. The role of this water-soluble protein in the bloodis to carry hydrophobic fatty acids as well as maintain the pHbalance. Since albumin is ubiquitous in the human body, almostall body tissues can enzymatically degrade the protein. This highdegree of biocompatibility and biodegradability gives albuminhigh potential as a biomaterial. Albumin is particularly successfulas a tissue engineering constructs with drug delivery capabilitiesand is usually preferred in studies determining protein and growthfactor release kinetics.

The weak mechanical properties of albumin has narrowed itsuse to drug delivery,87 coatings,88,89 and suturing90,91 applications.The protein can be processed into several different forms includingnanoparticles,87,92 microparticles,93 and fibres.94,95

Chondrotin sulphateChondrotin sulphate (CS) has shown great promise as a biomate-rial. This sulphated glycosaminoglycan has a structure very similarto HA. Found predominantly in articular cartilage, CS plays a rolein the matrices produced by fibroblasts in wound healing.96 It hasbeen shown to have anti-inflammatory effects and is a bindingfactor for extracellular matrix components.97 Chondrotin sulphatecan be commonly encountered particularly in cartilage tissueengineering combined with other cartilage ECM components toform multi-layered scaffold Its natural role in chondrogenic activ-ities has led to its investigation in cartilage tissue engineering98

both alone99 and featuring in composite materials that alsocontain poly(𝜖-caprolactone) (PCL),100 PEG,101,102 collagen,100,103

hyaluronic acid,104 and chitosan.105

Naturally-occurring poly(amino acids)Poly(amino acids) used in biomedical applications are branchedinto two groups: natural poly(amino acids) and syntheticpoly(amino acids) (discussed later).

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Natural poly(amino acids) are biodegradable and, unlike pro-teins, are composed of only one type of amino acid bonded byamide linkages. Poly(𝛾-glutamic acid) and poly(L-lysine) are themost commonly utilized polymers within the natural poly(aminoacid) category.

Poly(𝛾-glutamic acid) (𝛾-PGA) is a polyamide that is composed ofD- and L-glutamic acid enantomeric units. It is soluble in water andwith a reactive carboxylate group, there exists a wide variety ofoptions for further development with different functional groupattachments. Previously, 𝛾-PGA has been coupled with chemother-apeutic agents,106 antibiotics,107 DNA,108 and proteins107 to aidtissue healing and recovery. As scaffold material, however, the𝛾-PGA homopolymer is not preferred as it does not have adequatephysical properties. It has seen some application in soft tissue engi-neering within cross-linked hydrogels.109 Attempts to equip thispolyamide with characteristics suited to tissue engineering havebeen based on blending with natural (collagen110 and chitosan111)and synthetic polymers (PLA,112 PLGA,113 and PCL114) however,research has been limited due to the low availability of 𝛾-PGA.

Poly(L-lysine) research has revealed antibacterial,115 and anti-tumor activity116 effects that this polymer carries. This particularionic polymer, however, has also been found to have high toxicityowing to its extremely high positive charge and therefore is lim-ited, with in vivo use such as that with tissue engineering scaffolds.Attempts to appropriate it for use as a biomaterial have beenthrough blending it with 𝛾-PGA117 and other polymers118 – 120

although poly(L-lysine) remains a blending option that stillrequires further research and development before clinical uptake.

SYNTHETIC POLYMERS AS BIOMATERIALSSynthetic polymeric biomaterials may not always come as acheaper alternative to biological polymers due to less availability,however, they are much more easily reproducible and have alonger shelf-life and therefore are often more viable sources ofpolymeric biomaterials. Uniformity of microstructure, degrada-tion rate and mechanical structure with large-scale productionare the key advantages of these polymers. The most exten-sively used synthetic biomedical polymers is the family of linearaliphatic polyesters: polyvinyl alcohol (PVA), (PCL), poly(lacticacid), poly(glycolic acid), poly(hydroxybutyrate) (PHB).121 – 124

Numerous combination options of these polymers, both witheach other and/or various other elements, generate a great assort-ment of composite scaffolds with varying chemical, structural andmechanical properties that can be suited to specific tissues andtasks.

Regulatory bodies have presented affirmative guidance docu-ments for the use of synthetic polymeric biomaterials and as such,in terms of product validity, have supported the more efficient uti-lization of such synthetic materials. The future will thus continueto see synthetic polymers as indispensable tools for medical andtissue engineering applications.

Polyetheretherketone (PEEK)One of biomedical engineering’s most frequently utilized poly-mers is polyetheretherketone (PEEK). This linear, aliphatic,31 semicrystalline polymer is a high performance polymer with a highmelting point of 334 ∘C and a high resistance to wear. PEEK hasa maximum tensile strength of 100 MPa, a maximum elongationof 50–150% and a Young’s Modulus of about 3.7 GPa.125 Withits mechanical properties, chemical resistance and radiolucencyclosely matching those of natural bone,126 the popularity of PEEKin orthopaedic biomedical applications can be understood.

The biocompatibility of PEEK and PEEK composites127 hasbeen confirmed through numerous in vitro cytotoxicity128 – 130

and mutagenecity131 studies as well as in vivo studies that haveshown that the biomaterial triggers a minimal inflammatoryresponse.132 – 134 Adding to the benefits of using PEEK is its MRIcompatibility. These excellent chemical, mechanical and ther-mal properties make PEEK an obvious choice for load-bearingorthopaedic devices including uses in knee joints,135 spinalfusion,136 and craniofacial repair137 which have been the initialand traditional uses for it. Recent research,138,139 however, isseeking to transform PEEK-based biomaterials so that furtherfunctionality such as stimulation and integration of local tissuecan be achieved with it.

Due to the chemical intertness of PEEK, it has a limited abilityto form strong attachments to native tissues.140 Attempts to over-come this in orthopaedic applications introduced the inclusionof osteoinductive or osteoconductive factors, such as hydroxyap-atite. Such additives, however, have not provided a complete solu-tion as the mechanical strength of the polymeric material is quicklycompromised owing to the additional lack of binding betweenPEEK and reinforcement/filler elements.141 – 143 For the purposes oforthopaedic tissue engineering scaffold design, efforts have beenfocused on developing certain manufacturing methods for PEEKscaffolds such as knitting and braiding,144,145 acid-etching, alkalitreatment, anionic oxidation, shot-blasting,146 and sulfonation147

for some modification of its mechanical properties to producemore flexible, deformable, and matrix-like structures suitable fortissue ingrowth and local mechanics. Tissue anchorage with PEEKmaterials have been largely achieved through interconnectedporous scaffold designs146 that allow tissue integration in thematrix. It has been shown that pore sizes of 200–300 μm141 anda porosity value of 75%148 have been considered successful para-metrical values for attaining sufficient bone tissue fixation.

Poly(hydroxyalkanoates)Polyhyrdroxyalkanoates are another large class of naturally-occurring aliphatic polyesters. In terms of both availabil-ity and suitability to tissue engineering research, how-ever, poly 3-hydroxybutyrate (PHB), 3-hydroxybutyrate and3-hydroxyvalerate (PHBV) co-polymers, poly 4-hydroxybutyrate(P4HB), 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx)co-polymers and poly 3-hydroxyoctanoate (PHO) have been themain members of interest.

The simplest and most widely investigated of this family ofthermoplastics is poly(hydroxybutyrate), which has been exploredmainly in the construction of nerve149 and bone150 tissue engi-neering scaffolds. The biocompatibility of this biomaterial foundnaturally in the body151 is quite high, with its completely non-toxicdegradation products150 that are absorbable via natural metabolicpathways.

The main properties of PHB that limit its use are its brittleness,tendency to acquire a high degree of crystallinity,150 poor stiffnessand hydrophobic character and, compared with similar biomedi-cally utilized polymers, its slow degradation rate.152

The difficulties that these properties pose have been shownto be overcome with various scaffold fabrication methods, sur-face property modification procedures and other techniques. Aprimary example of such attempts includes the functionaliza-tion of PHB matrices by blending it with co-polymers such ashydroxyvalerate (PHV).153 The incorporation of hydroxyapatiteparticles in PHB-based scaffolds have also highlighted the contri-bution of such factors in enhancing the success of these scaffolds


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in tissue engineering approaches by the ability of hydroxyap-atite to not only attract osteoblastic activity but also modifythe microarchitecture for a more porous material. Similarly, theporosity achievable with use of aqueous emulsions have alsobeen shown to positively impact PHB scaffold performance.154

Another example is the use of polyethylene glycol, which has beenshown to enhance the hydrophilic properties of PHB nano-fibrillarscaffolds.155 Polyhydroxyalkonoates will continue to maintainsignificance in the field of medical polymers with the contin-uing progress in recombinant, purification and modificationtechnologies.

Poly(𝜶-hydroxyacids) (Poly(glycolic acid), Poly(lactic acid)and their co-polymers)Perhaps the most heavily researched category of syntheticbiopolymers is the linear aliphatic polyester family which includespoly(lactic acid), poly(glycolic acid), their co-polymers poly(lacticacid-co-glycolic acid), poly(𝜖-caprolactone), poly(propylenefumarate) and poly(hydroxy butyrate) (the last three willbe discussed separately later).156 As the most widely used,FDA-approved materials with long-term clinical data from awide range of clinical indications for which they have been uti-lized, this category of synthetic polymers are usually the first tocome to mind as synthetic biomaterials.

The poly(𝛼-hydroxy acids), poly(glycolic acid) (PGA), poly(lacticacid) (PLA) and their copolymer poly(lactic-co-glycolic acid)(PLGA), are broken down to their monomeric units lactic acid andglycolic acid through hydrolysis of the ester bonds in the back-bone of their chains. These breakdown products are then simplycleared by natural metabolic pathways. In order to maintain thehydrolytic stability of the ester bond, the length of the aliphaticchains must be limited. This is also important for keeping thedegradability characteristics of the polymer.

The highly crystalline thermoplastic, PGA, has impressive proper-ties such as a melting temperature >200 ∘C and a tensile strengthof about 12.5 GPa.157 These properties have led to the use ofPGA predominantly as suture material. As scaffold material PGAhas some unique and significant shortcomings. Its high molecu-lar weight form has poor solubility in most organic solvents whileits low molecular weight forms are more soluble. The more solu-ble forms of PGA, however, lack sufficient mechanical integrity invivo with significant decline in its performance observed at 2–4weeks158 – 161 – this may not be sufficient time for adequate regen-eration of certain body tissues such as bone. Although glycolicacid is a natural metabolite, high levels are known to stimulate anexcessive inflammatory response.162,163 Also, because of its highhydrolytic sensitivity, processing of PGA materials must be carriedout in carefully controlled conditions.

Poly(lactic acid) chains are assembled from chiral molecules andmay thus exist as poly(L-lactic acid) (PLLA), poly(D-lactic acid)(PDLA), poly(D,L-lactic acid) (PDLLA) and meso-poly(lactic acid).It is the optical impurities that exist between these enantiomersin the PLA chain, rather than the molecular weight, that deter-mine the ultimate properties of PLA-based materials. It is morehydrophobic than PGA which means that degradation rates aremuch slower, making it highly suitable for both in vitro and in vivoapplications164 – 167 where long-term mechanical integrity is criti-cal. The general values for Young’s Modulus, tensile strength andimpact strength for PLA are around 3 GPa, 1.5–2.7 GPa and 50-70MPa,168 respectively.

PLGA, on the other hand, presents a combined, myriad of prop-erty advantages over its polymeric counterparts. The copolymer

Figure 1. Degradation time of PLGA with varying lactic acid and glycolicacid ratio. Adapted from Ref. (179) By John Wiley & Sons, Inc. Reprinted withpermission.

composition is the main determinant of the chemical, mechanicaland structural variations that can be achieved. Figure 1 depictsthe influence of the co-polymer ratio on degradation rates. Whileincreasing the amount of the slower degrading PLA increasesdegradation time, counteractively increasing the amount of PGAwill slow down this process. Degradation times, for example, canbe from 1–2 months, 4–5 months and 5–6 months, for 50:50,75:25 and 85:15 co-polymer ratios of PLGA, respectively.169 Thebulk erosion of PLGA makes controlled release of therapeuticand other factors difficult. Therefore PLGA microspheres,170 – 173

microcapsules,174,175 nano-spheres,176 and nano-fibres177,178 areoften used.

Poly(𝝐-caprolactone)Another aliphatic polyester used as scaffold material in tissueengineering is the semi-crystalline polymer, poly(𝜖-caprolactone)(PCL).180,181 With great organic solvent solubility, a melting tem-perature of about 55–60 ∘C, and glass transition temperature of−54∘C182 this polymer is easily processed into tissue regenerationsupport structures.

Degradation profiles of the polymer make it suitable for use intissues that have a longer regeneration process. In particular PCLhas been shown to carry a similar rate of degradation to the rate ofnew bone formation.183,184,185 Compared with its family membersPLA and PGA, PCL takes much longer to degrade186 via the samenon-enzymatic cleavage of ester linkages.189 – 191 This is the mainreason why PCL is usually adopted for long-term in vivo systemsrather than short-term systems.192 Enzymatic degradation of PCLis known to occur to some extent as well, although this is not theprimary breakdown mechanism of the polymer.193

The innate biological inactivity of PCL makes it a promisingbiomaterial for safe and controlled in vivo applications. The invivo performance of PCL scaffolds have been commended fortheir particular success in carrying chondrogenic additives thatsuccessfully induce chondrogenesis in mesenchymal stem cells.194

The method by which such an inert polyester is functionalizedand ‘activated’ to produce desired effects is primarily throughsurface modification methods that focus on creating negativelycharged hydrophobic surfaces that promote cell attachment viaproteins such as fibronectin and vitronectin.195

Furthermore, blending and copolymerization196 with otherpolymers are methods by which scaffold characteristics can be


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controlled even further for desired outcomes. Owing to thisflexibility, the pore sizes achievable with PCL scaffolds and therelatively inexpensive manufacturing methods with this material,PCL serves as a viable material solution for tissue engineeringendeavours.

Poly(urethanes)Linear aliphatic polyesters dominate the hard-tissue engineeringsynthetic biomaterials category whereas the main biomate-rial investigated for soft-tissue engineering purposes has beenpolyurethane. A hard segment (diisocyanate), the soft segment(poly(ethers) or poly(esters)) and chain extenders are the fun-damental components of polyurethanes.197 The ratios of thesecomponents involved in the chemical reaction that produces thepolyurethane will define its ultimate properties.

The historical use of polyurethanes had experienced the draw-backs of the polymer’s toxic degradation products. To overcomethis issue, polyurethanes with diisocyanate replacements havebeen developed. One example is using 1,4-diisocyanatobutane(BDI) and a putrescine chain extender where the degradationof BDI leads to the release of putrescine – a polyamine whichencourages cell growth and proliferation.198 Another example ispolymerizing highly pure lysine diisocyanate with glucose so thatbreakdown products consist of merely glucose and lysine.199

Polyurethane matrices with a wide range of porosities,surface-to-volume ratios, and three-dimensional structures can bemade via electrospinning, water foaming and thermally-inducedphase separation methods. Tensile strength and breaking strainscan reach 13 MPa and 280%, respectively.199 Polyurethanes havealso displayed cell adhesion and proliferation qualities which alsoadd to their suitability for in vivo use.200 However, an importantdrawback for polyurethanes in tissue engineering or drug deliveryuse is that their degradation rates are found to be not suitable forthese applications. For this reason blends and combinations ofpolyurethane with other biomaterials are made to assist degra-dation profiles of polyurethane-based scaffolds. Ongoing studiesare looking into chemically modifying polyurethanes to equipthem with the appropriate mechanical characteristics requiredat the various stages of healing and regeneration, subsequentlyfollowed by its biodegradation. Biodegradable polyurethanes,therefore, continue to hold promise over highly porous scaffoldsthat are disadvantaged by mechanical weakness.

Poly(propylene fumarate)Poly(propylene fumarate) (PPF) is a unique, injectable, linearpolyester that contains multiple unsaturated double bondsthat are also available for covalent cross-linking in the pres-ence of free-radical initiators using benzoyl peroxide and NN dimethyl-p-toluidine. The biocompatibility of PFF has beenestablished by various studies.201,202

The cross-linking capability of the polyester means that degrada-tion characteristics will be dependent on the cross-linking density,the cross-linker and the molecular weight of the polymer.203

This capacity also translates to the ability of PPF-based scaf-folds to assume scaffold designs that may not be achievable bynon-cross-linkable biodegradable polymers. In fact, this flexibilityhas made PPF a common bone defect filling material.204 – 207

The crosslinking reaction is propagated using free-radicalpolymerization.

PPF-based porous scaffolds.201,208 – 210 and microsphere-embedded scaffolds211 – 214 have been studied in vivo or in vitro

extensively, and have proved to be biocompatible. The traditionalmethod of synthesizing porous PPF scaffolds was by embeddinginto the polymeric material sodium chloride crystals which areleached out upon implantation – a technique that carries the riskof creating a hypertonic local environment and offers minimal con-trol over interconnected porosity. Current methods are based oninitiating foaming reactions during polymerization215,216 such thatthe supercritical CO2 treatment will generate the porosity essentialfor the success of PPF scaffolds in tissue repair and regeneration.The inclusion of ceramics and other enhancement factors in thesescaffolds mechanically strengthens them217 as well as improvingtheir biocompatibility and material–tissue relationships.218 – 220

Synthetic poly(amino acids)Synthetic poly(amino acids) include homo-and co-poly(aminoacids), and display high crystallinity, low degradation rate,poor mechanical properties and immunogenicity221 have beenreported for these polymers.

Poly(L-glutamic acid) (L-PGA) is a flexible synthetic poly(aminoacid) that is relatively easy to fabricate into differentarchitectures.222 It is also non-immunogenic and enzymaticallydegradable.223,224 It has featured as cancer drug delivery225 andMRI contrast agents226 and as a copolymer with other polymers intissue engineering scaffolds.

Poly(aspartic acid) (PAA) is a highly water-soluble polymer thatalso exists as a hydrogel and undergoes enzymatic degradation.227

It can be copolymerized with other polymers (e.g. PLA,228 PCL229

and PEG228). Micellar configurations formed by these co-polymershave seen interest for use in payload delivery.

Poly(ortho esters)The poly(ortho ester) (POE) family of hydrophobic polymers230 arepolymers consisting of three geminal ether bonds. The uniquequalities of POEs are its surface-erosion mechanism of degrada-tion and the sensitivity of the process to pH. Ortho-ester bondsare stable at neutral pH but rapidly hydrolyse at about pH 5.5.Under physiological conditions these highly hydrophobic poly-mers require activation of degradation via an acid.

Of the four classes of POEs, presented diagrammatically in Fig. 2,it is the fourth group, POE IV, that has particular relevance to tissueengineering. POE IV, modified from POE II, consists of short seg-ments of lactic acid or glycolic acid incorporated into its backbone.This not only speeds up degradation but makes POE IV more suit-able for tissue regeneration materials than POE I–III, which possessdegradation rates much too slow for these purposes. Varying thebackbone chemistry of POEs will vary the degradation and mate-rial properties.

This new generation of POEs is an evolutionary developmentof the second generation polymers232 and is recognized asself-catalytic poly(ortho esters). In this new variation of POE, shortdimer segments of glycolic acid or lactic acid are incorporatedinto the polymer backbone. Owing to the susceptibility of POEto acid-catalysed hydrolysis, varying the concentration of the𝛼-hydroxy acid dimer segments in the polymer backbone cancontrol the erosion rate of the bulk polymer. These polymersoffer significant advantages over the second-generation POEs,which required the addition of acidic excipients to control erosionrate.

Poly(anhyrides)Polyanhydrides are either aromatic, aliphatic or a mixture of thetwo polymers that are constructed from two carbonyl groups


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Figure 2. The four poly(ortho ester) families. Adapted from Ref. (231) By Elsevier Science B.V. Reprinted with permission.

bound by an ether bond. Synthesis of this hydrolytically unsta-ble polymer is via the dehydration of the diacid or mixtureof diacids by melt polycondensation produces this class ofbiodegradable and biocompatible polymer. Polyanhydrides havepredominantly featured as biomaterials that are practical fordrug delivery systems. Polyanhydride-based microparticles233 – 235

and nanoparticles236 – 238 developed for these purposes can beinjected, administered orally or with aerosol delivery.

These polymers undergo surface erosion that is pH-dependentand degradation is based on the backbone chemistry of the poly-mer, with the specific tuning of degradation rate. Polyanhydrideson their own are usually not suitable for tissue engineering appli-cations that require load bearing scaffolds as their low molecularweights limit their mechanical strength. The Young’s modulus ofpoly(anhydride)s has been determined to be around 1.3 MPa239

which would not, for example, be suitable in bone tissue engi-neering approaches. Dimethacrylated anhydrides, however, isone sub-class that offers a stronger polyanhydride-based mate-rial. This is due to the photo cross-linkability and variability ofmonomers which allow for the attainment of higher structuraland mechanical integrity of these networks.240,241 Cross-linkedpolyanhydrides have shown effective performance in bone tissueengineering approaches as well as drug delivery materials.242

Monomer flexibility also gives promise of applications in othertissue engineering fields.

Poly(anhydrides-co-imides) have been developed as mechan-ically stronger brands of polyanhydride-based materials thatalso undergo surface erosion.243 Compressive strengths up to50–60 MPa have been reported for poly(anhydrides-co-imides)based on succinic acid, trimellitylimidoglycine, andtrimellitylimidoalanine.244

Poly(anhydride-esters), are particularly attractive as they com-bine the properties of polyesters and polyanhydrides. There are, forexample, poly(anhydride esters) that are based on salicyclic acidthat release the non-steroidal anti-inflammatory (NSAID) (i.e. sali-cyclic acid) upon hydrolytic degradation.

The opportunity to tailor polyanhydrides in such ways make ita versatile material that can be modelled into a diverse range oftissue restoration systems.

Poly(glycerol sebacate)Poly(glycerol sebacate) (PGS) is a biodegradable polymer synthe-sized by the polycondensation of glycerol and sebacic acid. PGSwas first used in a soft-tissue engineering applications in 2002.245

PGS is completely bioresorbable with degradation productseliminated through natural metabolic pathways.246

The hydrophilic, partially semi-crystalline PGS polymer has ther-moset elastomeric properties that can be tuned via the alterationof curing temperature, curing time and molar ratio of glycerol tosebacic acid.247 – 251

An additional level of control over these properties inpoly(glycerol sebacate acrylate) (PGSA) is through varying thenumber of acrylate moieties, which translates to varying thenumber of cross-links in the polymer network.252

Typical of elastomeric biomaterials, PGS has a nonlinear stress–strain behaviour and at 37 ∘C the polymer is totally amor-phous. Another interesting feature of PGS is its shape–memorybehaviour. With heat, PGS materials can be stimulated tore-conform to ‘memorized’ shapes and this property is attributedto its ability to switch from its fixed three-dimensional networksat cooler temperatures to its amorphous phase with increasedtemperature.253

PGS undergoes surface erosion with the cleavage of ester link-ages. This type of degradation is useful in that unlike bulk ero-sion, mass loss in surface erosion occurs linearly with time, so thatgeometrical features supporting tissue regeneration are main-tained for longer periods.245,254,255 Although PGS has an acceler-ated degradation rate in vivo than in vitro, the biopolymer hasshown complete biocompatibility in several studies.256 – 258 Onelimitation to PGS use in tissue engineering applications, however,is reported to be the acidic local environments that can be gen-erated when the hydrolysis of the ester groups release carboxylicacids.259

Further functionalisation of PGS has been investigated with theuse of cell migration, adhesion, differentiation and proliferationmediators such as laminin, fibronectin, fibrin, collagen types I/III,and elastin.260

To synergize the favourable characteristics of various poly-mers available for combination with PGS several compositePGS-based scaffolds have been explored. Bioglass/PGS mem-branes for cardiac tissue engineering,259 PGS with nano-tubularhalloysite (2SiO2·2Al(OH)2) incorporation,261 micro-structuredfibrous PGS-PCL scaffolds for heart valve regeneration262 are someexamples of where both organic and inorganic biomaterial blendswith PGS have been studied.

It is the modification of textile manufacturing technologiesand their adaptation to production of biodegradable elastomersthat has given rise to some significant biomedical companies ofour day. There are currently intensive research and development


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efforts that are producing, in particular, flexible tubular structuresand woven matrices that are seen in clinical use.

Poly(phosphazenes)Poly(phosphazenes) are a very large group of polymers that havetraditionally been produced with high molecular weights. Theirbackbones are completely inorganic constructed with alternatingphosphorous and nitrogen atoms with two organic side groupsattached to each phosphorous atom. Most phosphazenes aremade by substitution reactions on a poly(dichlorophosphazene)intermediate. The history of poly(phosphazene) use inbiomedicine only extends back to the past two decades.263

In order to functionalize the polymer further, specific side groupscan be introduced onto the primary structure such as amino acidesters, glucosyl, lactate or imidazolyl units.264 – 266 This flexibilityhas led to >500267 types of poly(phosphazenes) produced to dateand as such initiated an exploration of these polymers as biomate-rials for tissue regeneration rather than just their traditional use indrug delivery.

The aforementioned side groups, for example, introducehydrolytic instability to the structure and assist with degradationwhere the non-toxic breakdown products are released. Interest-ingly, when poly(phosphazenes) are combined with polymers, likepolyesters, that have acidic degradation products, the presenceof poly(phosphazene) breakdown products have a pH bufferingeffect.268 Mechanical properties are also varied in this manner too.One study found that such modifications produces significantlylarger value ranges for glass transition temperature (Tg − 0–35 ∘C),contact angle (63∘–107∘), tensile strength (2.4–7.6 MPa), andmodulus of elasticity (31.4–455.9 MPa).269 Poly(phosphazenes)do generally require blends with other polymers in this way toimprove chemical and mechanical characteristics. There has alsobeen some recent concern over the foreign body response270 thatpoly(phosphazene)-based materials have been found to trigger,contrary to previous research which had only found a limitedinflammatory response.271

In various tissue engineering applications such as nerveregeneration272,273 and orthopaedic applications,274,275 poly(phosphazenes) have been used as films,274 fibres,272,275 gels,276,277

and sintered microspheres274 thanks to the ability to increase theirhydrophobicity with side group substitutions.

Poly(dioxanone)Poly(dioxanone) (PDO) is one of the most commonly used mem-bers of the poly(ester ether) family of degradable polymers. Thesepolymers typically have an ether bond integrated into the back-bone of a polyester with the aim of initiating hydrolytic cleavage ofthe ester bond. Ring-opening polymerization of p-dioxanone pro-duces PDO. P-dioxanone has a Tg about −10 to 0 ∘C and a Tm of115 ∘C.278

PDO is considered a slow-degrading polymer that has completemass loss at about 6–12 months.157 PDO does not exhibit themechanical properties that tissue engineering scaffolds wouldgenerally require, with a modulus of (1.5 GPa).157 It does, however,have good flexibility and 1–2 months of considerable strengthmaintenance which is why it has been selected for the productionof monofilament sutures for decades.279

Poly(ethylene glycol) – Poly(ethylene oxide)Poly(ethylene glycol) (PEG) is polyether that is polymerized fromethylene oxide condensation. Chains of PEG that are above 10 kDa

are termed poly(ethylene oxide) (PEO). The hydroxyl groups at theend of PEG chains are used for a variety of PEG macromers thathave differing properties and uses.

PEG polymers are biocompatible, biodegradable, non-toxic, andlow-immunogenic synthetic polymers that do not bind proteins orcells.280,281 In fact, the first interest in PEG was to use it as biomate-rial surface coatings owing to its ability to prevent serum proteinadsorption, although the mechanisms by which this occurs is stillnot completely understood and have been attributed to a num-ber of factors.282,283 The mechanical properties of PEG scaffolds intissue engineering depend on the molecular weight, cross-linking,and polymer concentration. Decreasing the molecular weight orincreasing the concentration of the polymer has been shown toimprove the elastic modulus.284

PEG hydrogels have been studied in tissue engineering scaffoldapplications. Of course these scaffolds have been adapted to thesepurposes with the incorporation of cell adhesion RGD peptides toenable cell adhesion and survival.285 For PEG hydrogels that maycarry proteins or cells for implantation and release, photopolymer-ization is preferred to thermal polymerization owing to the sen-sitivity of this method towards such payloads and the better effi-ciency that it offers.286 In fact, one group has been able to demon-strate PEG photopolymerization transdermally.287 PEG is oftenalso preferred for its bio-inactivity toward encapsulated proteinsor cells where such interaction is not desired.285,288 – 291 Functional-isation is also possible where cell adhesive molecules and growthfactors used in PEG hydrogel scaffolds have added to the successof modulated tissue regeneration with these materials.292 – 295

As discussed, there are several synthetic polymer options thatcan be used in various medical applications. The suitability ofeach of these polymers for their intended use is based on theirrespective chemical and physical properties and the capacity towhich they can be processed to assume the required structuralcharacteristics. Table 1 summarizes the key properties of thesynthetic polymers discussed for quick reference.

HydrogelsCross-linked polymer networks that contain 60–90% water, knownas hydrogels, have become attractive materials for regenerativemedicine. Due to their remarkably tuneable properties hydrogelsare emerging as an exciting new material used in a diverse rangeof applications including the development of artificial corneaimplants,306 as fillers for soft tissue engineering307 operations andin cartilage repair materials,308 to name a few.

Degradable three-dimensional hydrogel matrices are made fromeither hydrophilic homopolymers, copolymers, or, they can exist asinsoluble matrices via the introduction of cross-links.

Hydrogels can be fabricated from both natural polymers ofagarose, alginate, chitosan, hyaluronic acid, fibrin, collagen andothers, as well as synthetic polymers such as poly(ethylene gly-col) (PEG), poly(vinyl alcohol) (PVA), and polyacrylates such aspoly(2-hydroxyethyl methacrylate) (PHEMA).309,310 Covalent andnon-covalent bonding in cross-links generate a biocompatible311

matrix with structural similarity to other macromolecules found inthe body.

Among the different methods of hydrogel synthesis, includingMichael (conjugate addition) and click chemistry, free-radicalpolymerisation is the most appealing for tissue engineering dueto the great gelation kinetics and in situ polymerization capabilityassociated with this process.312 Figure 3 is a visual representationof these chemical synthesis processes. Acrylate-based hydrogelsthat have been subjected to this process contain many mechanical


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Table 1. Properties of popular synthetic polymers used in medicine

Polymer Structure

Crystallinity

(%)

Elastic

modulus

(GPa)

Tensile

modulus

(GPa)

Melting

temperature

(∘C)

Glass

transition

temperature

(∘C)

Degradation

products

Time to

degrade

(months) Refs

Polylactic acid 37 2.7 1.5– 2.7 173–178 60–65 L-Lactic acid 12– 18 (296–298)

Polyglycolic acid 45-55 7.0 5–7 225–230 35–40 Glycolic Acid 3– 4 (296,298)

Poly(𝝐-caprolactone)

37 0.4 0.4– 0.6 58–63 −60 Caproic Acid >24 (299–301)

Poly-lactic-co-glycolic acid(50/50)

Amorphous 2.0 1.4– 2.8 Amorphous 50–55 D,L-lactic acidandglycolic acid

3–6 (296–298)

Poly(propylenefumarate)

37 2– 3 2–3 30–50 −60 Fumaric acid,propylene

glycol and

poly(acrylic

acid-cofumaricacid)

Varies (>24) (302,303)

Polyanhydride - - 25–27 50–90 −27 Carboxylic acids 0.14–1.4 (304,305)

Polyhphosphazene 55 - - - - Phosphate,ammonia,correspondingside groups

surface (267,274)

and structural advantages such as increased elastic modulus,313

great cell–biomaterial interactions,314 good tensile modulus,315

prevention of undesired fibrosis,316 enhanced mechanisms ofrelease of payloads embedded in polymeric material,292,294,317 andhigher compressive modulus with GAG incorporation.318 – 322

Mixing or blending hydrogels with micro- and nanoparticles324

which are later removed through various processes or throughnatural dispersion with payload delivery allow porous scaffoldsto form. Successful porous synthetic hydrogels in cornea replace-ments offer an example of this. Such scaffolds are also known topromote cell migration and angiogenesis and with a high watercontent are capable of rapid nutrient diffusion.325

Although porosity is desirable for tissue integration, the biggestchallenge yet for porous hydrogel scaffolds is the poor mechan-ical strength that they display.326 Cross-linking density plays animportant role in appropriating mechanical compliance andmesh size for cell encapsulation and use in tissue augmenta-tion procedures.327 Careful control of chemical and processingparameters can ultimately yield hydrogel scaffolds with numerousbenefits for tissue regeneration efforts.

STIMULI RESPONSIVE POLYMERS‘Smart’ or ‘intelligent’ polymers are those which can alter theirphysio-chemical properties in response to stimuli (pH, tempera-ture, redox, enzymes, light, magnetic, ultrasound) such that a par-ticular functional output of the polymeric system occurs. Amongsome property changes that can occur as a response to stimuli arechanges in surface wettability,328 membrane permeability,329,330

swelling capability (hydrogels),331 aggregation behaviour,332

and sol-gel transition.333 Stimuli-responsive polymers are pro-duced by introducing specific polymeric modalities to traditional

polymeric systems, creating multi-functional systems.334 Assuch, stimuli-responsive polymers have received great interestover the past decade and have been taken up in a number ofmedical applications from drug delivery and tissue engineering toimaging.

Thermo-responsive polymersTo date, temperature- and pH-sensitive polymers have been themost frequently studied type of stimuli-responsive polymer.Thermoresponsive polymers can change their hydrophilic-ity/hydrophobicity, conformation or solubility due to a phasetransition reaction when prompted by elevated temperatures335

to reach a threshold temperature known as critical solution tem-perature (CST). Generally, a lower critical solution temperature(LCST) polymers will reduce the solubility (increase hydrophobic-ity) while a higher critical solution temperature (HCST) will increasesolubility (increase hydrophilicity).336 Poly(N-isopropylacrylamide)(PNIPAAm) in particular has been the most researchedtemperature-responsive polymer where it exhibits a transitionfrom hydrophilicity under 32 ∘C to a hydrophobicity above thistemperature.337 One study demonstrated the utility of the LCSTfeature of PNIPAAm with a thiolated chitosan-PNIPAAm hydro-gel used for wound infections that deliver ciprofloxacin (ananti-bacterial drug) to the wound site that will then swell uponthe addition of cold water for easy removal of the gel. Anotherexample is poly(N-vinylcaprolactam), a lactam-based polymer thatis also thermoresponsive with a LCT of about 35∘C338 and holdspromise in tissue engineering applications as it thermorespon-sivity allows for the formation of a macroporous architecture – acommon limitation for hydrogels intended for use in tissue engi-neering applications. Other temperature-responsive polymersused in biomedical applications include poly(N-vinylcaprolactam)


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Figure 3. Common methods of hydrogel synthesis A) Free-radical polymerisation of diacrylate macromer. B) Conjugate addition of a thiol and acrylategroup. C) ‘Click’ bonding of a pendant alkyne and azide via 1,2,3-triazole group. Adapted from Ref. (323) by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.Reprinted with permission.

(PVCL) which has increasing hydrophobicity and insolubility from25–35 ∘C,339 poly(ethylene glycol) (PEG) or poly(ethylene oxide)(PEO) which becomes insoluble above 80 ∘C and poly(propyleneoxide) (PPO) which, when in co-polymer form,340,341 can exhibit awide range of solubility and phase transition temperatures.

pH-responsive polymerspH-responsive polymers respond to changes in pH, co-solvent,and electrolytes such that changes in their solubility, volume,and chain conformation can be observed. The pH-responsivenessof polymers can be tuned by the incorporation of ionizablemonomer units in to their polymeric backbones. Chitosan-carrageenan-based polyelectrolyte complexes have beenexplored as porous biomaterials that can maintain stabilityat physiological conditions while dissociating upon implan-tation due to chitosan reacting under the lowered pH levelscaused by local inflammation associated with implantation.342

Another study343 was able to show how electrospun poly-electrolyte hydrogel nanofibres were able to display reversibleswelling/contracting with varying pH, highlighting their potentialas artificial muscles, interactive tissue engineering scaffolds ordrug delivery systems. Materials based on poly(acrylic acid) (PAAc)and poly(methacrylic acid) (PMAc) are common polymers usedin pH-responsive systems and can also exhibit reversible swellingwhen pH is varied.344,345 Such acrylic polymers and their unique

properties, for example, increased surface adhesion when inprotonated form, have also inspired interest for their use in drugdelivery systems.

CONCLUDING REMARKSCurrently, the number of donors required for organ and soft tis-sue replacement are well below those numbers that are actually indemand. For this reason, research and development of syntheticmaterials capable of combining cellular components for both thein vitro and in vivo regeneration of tissues are continuing to pro-ceed at a significant pace. The range of different chemical naturesof different polymers, the ability to fabricate them such that theyreplicate tissue or organ morphologies, their ability to biodegradewithout adverse effects, and their biocompatibility has created agreat area of use in the field of tissue engineering. The modifi-cation and enhancement of several processing methods such as3D printing, electrospinning, fibre processing, and foaming for theproduction of tissue scaffolds seen in recent years, the fall of pricesassociated with medical grade products and the improvements inconditions of manufacturing these products in small-scale cleanenvironments have all been factors leading to the uptake of poly-mers in efforts to regenerate bone, cartilage, tendon, skin, cornea,and other tissues that constitute different morphological andmechanical properties. The advancements in growth factor-cell


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studies and stem cell studies that have progressed parallel tothese efforts combined with the widespread use of bioreactors, allwithin the regulative standards of special organizations such as theadvanced technological medicinal products (ATMP), provide fore-sight into the utilization of polymers in multi-component complexsystems that are developed in tissue engineering studies and sub-sequently taken up in clinical use.

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