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Advances in Applied CeramicsStructural, Functional and Bioceramics

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Phosphate glass fibres with therapeutic ionsrelease capability – a review

Agata Lapa, Mark Cresswell, Phil Jackson & Aldo R. Boccaccini

To cite this article: Agata Lapa, Mark Cresswell, Phil Jackson & Aldo R. Boccaccini (2019):Phosphate glass fibres with therapeutic ions release capability – a review, Advances in AppliedCeramics, DOI: 10.1080/17436753.2018.1564413

To link to this article: https://doi.org/10.1080/17436753.2018.1564413

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Published online: 21 Jan 2019.

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Phosphate glass fibres with therapeutic ions release capability – a reviewAgata Lapa a,b, Mark Cresswell b, Phil Jacksonb and Aldo R. Boccaccini a

Department of Materials Science and Engineering, Institute of Biomaterials, University of Erlangen-Nuremberg, Erlangen, Germany;Lucideon Ltd UK, Stoke on Trent, UK

ABSTRACTPhosphate-based glasses (PBG) have low melting temperatures and can be obtained by melt-quenching and sol-gel methods. The most significant characteristic of PBG is their ability todissolve completely in aqueous solution within different timeframes. This solubility canreduce the need for revision surgeries and makes PBG well-suited for soft tissueregeneration. Phosphate glass fibres (PGF) due to their geometry and volume–surface arearatio are the subject of a growing number of studies on resorbable composites. Medicalapplications include bone fixation devices, nerve tissue scaffolds and wound healing. PBGcan be doped with various ions to enhance their biological, chemical and structuralproperties allowing the preparation of fibres with designed properties and with the ability torelease biologically active ions upon degradation. The aim of this review is to look in detail atthe influence of different dopants on PGF behaviour, both at a structural and biological level.

ARTICLE HISTORYReceived 11 April 2018Revised 24 December 2018Accepted 26 December 2018

KEYWORDSPhosphate glass fibres;soluble glasses; therapeuticions; metal ions; bone; bonefixation devices; soft tissueregeneration; hard tissueregeneration

Phosphate-based glasses

Phosphate-based glasses (PBG) may be divided intothree groups according to their P2O5 content. Ultra-phosphate glasses (2.5≤ [O]/[P] < 3) contain morethan 50 mol-% of P2O5, while metaphosphate glasses([O]/[P] = 3) contain 50 mol-% of P2O5 in the glass.The structure of these two types of glasses is builtupon chains and rings however chains representmore of a polymeric linear structure than a 3-D net-work. Polyphosphate glasses with [O]/[P] > 3 haveless than 50 mol-% of P2O5 and the glass network pre-ferentially forms chains and rings terminated by Q1

diamers [1,2]. Invert glasses are a class of phosphateglasses called ‘pyrophosphate’ with less than 33.3mol-% of P2O5 formed by orthophosphate and pyro-phosphate groups. Invert phosphate glasses are moreresistant to hydrolysis but difficult to manufacturedue to a narrow processing window [3] (define as theonset of crystallisation temperature decrease by glasstransition temperature [4]).

In glass technology, oxides can be divided into threegroups: (i) network forming oxides (e.g. SiO2, P2O5,B2O3), (ii) network modifying oxides (e.g. CaO,MgO, SrO, BaO, PbO, ZnO, Na2O, Li2O, K2O) and(iii) intermediate oxides (e.g. oxides of: Ga, Ti, C, V,Bi, Mo, W, S, Se, Te) [5] which can act as both networkformers and network modifiers. In addition, manyother elements can be used as dopants to improvethe properties of PBG. Crystallisation tendency, mech-

anical properties and stability against hydrolytic attackare all features which are dependent upon the charge-to-size ratio of the network modifier ion. This ratiodetermines the strength of the ionic cross-linksbetween two non-bridging oxygens. A large charge-to-size ratio results in creating bonds more resistantto hydrolysis and lowers the crystallisation tendency.When the phosphate structure is more disrupted, andthe phosphate structural domains are smaller, the ten-dency for the glass to crystallise is higher. Moreover, adecrease into the cross-linking of PBG results in a low-ering of the glass transition temperature.

The ability to control properties is a great challengewhen designing materials for medical applications asthey need to have very specific chemical compositionand physical and biological properties. PBG with theappropriate composition can be highly soluble so thatwhen they are implanted into the body they will dis-solve completely after a certain period of time. Indeed,phosphate glasses can be considered as a reservoir ofbiologically active ions, which can be released in thebody upon dissolution of the glass.

The inclusion of trace elements into PBG not onlyimproves their properties but can also have beneficialeffects from a biological perspective (Figure 1). Traceelement biology relates to a number of various chemi-cal elements that occur naturally in very small amountsin organisms and are essential for many physiologicaland biochemical processes [6]. In addition to the active

© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis GroupThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, orbuilt upon in any way.

CONTACT Agata Lapa agata.lapa@fau.de Department of Materials Science and Engineering, Institute of Biomaterials, University of Erlangen-Nur-emberg, Cauerstrasse 6, 91058 Erlangen, Germany

ADVANCES IN APPLIED CERAMICShttps://doi.org/10.1080/17436753.2018.1564413

research in the areas of pharmaceutics and medicaldevices, there are examples of the application of phos-phate glasses in the agriculture and veterinary fields [7].The trace elements such as copper, cobalt or seleniumhave been added to PBG to obtain a soluble glass bolusfor the veterinary application. Molybdenum deficiencyin plants has been fought through controlled release ofions from PBG [8].

Phosphate glass fibres

Phosphate glass fibres (PGF) have an interesting mor-phology which gives them an advantage over tra-ditional bulk glasses. This morphology means theyexhibit great potential as materials for regeneration oftissue with a medium to high anisotropy like muscleor ligament [5].

In the work of Massera et al. [9] the authors focusedon the differences between glass fibres and bulk glassesin the composition 50P2O5–40CaO–10Na2O (mol-%).The fibres were obtained via the melt–drawn spinningprocess. Both bulk glass samples and fibres were incu-bated in simulated body fluid and Tris(hydroxymethy-l)aminomethane (TRIS) solution. The followingobservations were made based on DTA thermogramsand Raman analysis: (i) fibre drawing leads to preferen-tial orientation of P–O–P bond (most likely along theaxis) and (ii) tendency to crystallisation is lower forfibres than for bulk materials [9].

No other significant differences were observed prov-ing that fibres have the same structural properties asbulk glasses. However, the main difference betweenthem is the thermal history considering that melt-spun fibres undergo fast cooling (which helps avoidcrystallisation) but bulk glasses are annealed to controltheir cooling rate [10]. Those results have beenconfirmed by Munoz et al. [11] who showed no signifi-cant structural differences between bulk glasses andglass fibres.

Solubility of PBG and PGF

PBG and PGF can resorb completely in aqueous sol-ution [12]. However, for practical reasons glasseswith very limited durability are not always desired.For example, PBG with very fast dissolution rates hasbeen shown to decrease proliferation [13] and disturbthe expression of the bone-associated proteins [13].The high solubility of PBG is caused by the presenceof Q3 tetrahedra characteristic of pure vitreous P2O5.Introducing R2O oxides results in depolymerisationof the Q3 units and the formation of new Q2 units,however the incorporation of Na2O does not reducethe solubility of binary PBG. As an alternative, theRO/P2O5 system has been developed and investigatedby Toyoda et al. [14] who showed that the viscosityof glass decreases with the ionic radius of the glassmodifier. Despite improving the durability, CaO–P2O5 glasses are difficult to process due to their highthermal expansion coefficients. To overcome thedescribed difficulties associated with binary systems,the P2O5–CaO–Na2O ternary composition has beenextensively investigated showing both promising bio-logical properties [15–18] and reasonable degradationrates [19]. Several studies have been carried out onthis material proving its potential for use in medicalapplications [13].

Biological response to PBG and PGF

The influence on soft and hard tissue of PBG has beencomprehensively investigated using glasses in the sys-tem: 50P2O5–(48–30) CaO–(20–2) Na2O (mol-%)[20]. Four different human cell lines were used:MG63 cells (human osteosarcoma delivery cell line)as representative of osteoblastic behaviour, humanoral osteoblast (HOB), human oral fibroblast (HOF)and human tendon fibroblast (HTF). Tests showedthat glasses with less than 40% CaO do not support

Figure 1. Influence of metallic ions on PGF properties and cell response.

2 A. LAPA ET AL.

MG63 attachment while the best cell attachment wasobserved for glasses with 48% of CaO. Despite thefact that round HOB cells were observed on all glasses,only fibres with composition 50P2O5–48CaO–2Na2O(mol-%) led to the best response of bone sialoproteinand osteonectin – the proteins responsible for bonemineralisation. Similar results were reported for HOFand primary cells, where adhesion was not observedfor all glasses apart for those with the highest amountof calcium oxide. Spread morphology and cytoskeletonof HOF cells were also observed to be similar to thoseof the positive control. It has been proven that ternaryPBG with a high level of CaO (45 mol-%) and 50% ofP2O5 are suitable for both hard and soft tissue regener-ation by supporting cell attachment, proliferation andfurther survival of the cell [20]. The studies havebeen confirmed by Salih et al. [13,21] who investigatedternary phosphate glass compositions on two humanosteoblast cell lines, MG63 and HOS (TE85). Theresults showed that a higher amount of CaO (40mol-%) in glasses with fixed 45 mol-% of P2O5 is ben-eficial for adhesion and cell proliferation. Skelton et al.[15] performed studies on PBG with 50 mol-% of P2O5

investigating their role in osteoblast and osteoblast-likeproliferation, differentiation and death using humanbone marrow stromal cells (hBMSCs) and human foe-tal osteoblast 1.19 (HFOB). Again, a strong correlationbetween dissolution rate and cell response wasreported. Degradation and processes related to it likeion release, hydration and hydrolysis have a greatimpact on cells. Moreover, the loss of surface integrityassociated with glass dissolution can disturb adhesionof cells leading to poor proliferation or differentiation.Nevertheless, glasses with 48 mol-% CaO have beenproven to support osteogenic proliferation and earlydifferentiation [15] and other studies presented inthis review suggest promising biological properties ofPGF of different elemental compositions.

Manufacturing and modifications methods

There are several fibre manufacturing methods how-ever not all phosphate glass compositions allow suc-cessful preparation of continuous fibres [22]. Forexample, glasses with higher P2O5 content (for example50, 55 mol-%) have a higher amount of infinitely longQ2 chains which make them easier to be pulled asopposed to glasses with many short Q1 units [22].

In general, PGF are obtained by three methods: (a)melt-drawing spinning process, (b) preform techniqueand (c) pulling from melting solution (Figure 2). Onlyby using drums with controlled rotation speeds can thefibres be produced with consistent, controllable diam-eters, with faster rotation delivering smaller diameters:40 µm (300 rev min−1), 40–23 µm (400 rev min−1),25–20 µm (880 rev min−1), 20–15 µm (1200 rev

min−1), 15–8 µm (1600 rev min−1) and ∼10 µm(2000 rev min−1) [17,19,23–31].

Delivery of therapeutic ions – componentions

Most PGF developed for medical application are basedon ternary phosphate glasses in the system: Na2O–CaO–P2O5. This base composition is interestingbecause it contains only elements present in thehuman body (P, Ca, Na 1, 1.5 and 0.2 wt-% respect-ively) with important biological roles. Moreover, it ischemically similar to the inorganic phase of humanbone [33].

Phosphorus

Orthophosphate PO43− is the most abundant form of

phosphorus in the body and it is mostly present inbone where it forms hydroxyapatite. Moreover, PO4

3−

plays an important role in the cell signalling system,regulation of protein synthesis, skeleton developmentand bone integrity [34]. Phosphorus is also present inadenosine triphosphate (ATP) and Guanosine-5′-tri-phosphate (GTP) – the biomolecules responsible forenergy transport. In addition, phosphorus is a com-ponent of the phospholipids which are important inthe development of the cell membrane and stimulatethe expression of matrix Gla protein (MGP), a key reg-ulator in bone formation [35].

Other important properties and roles of phosphorusinclude linkage units of the sugar esters of DNA andRNA; coenzymes such as FMN, NADH, NADPH; sig-nalling molecules such as CAMP [36].

As a network forming oxide P2O5 plays a crucialrole in the glass manufacturing process. A glass net-work is made by linkages between the phosphate tet-rahedra with the addition of metal oxides causingdepolymerisation of the phosphorus-oxygen bondin P–O–P [37]. Pure P2O5 glass is rarely usedbecause of its high solubility since P–O–P bondshydrolyse easily. However, the degradation productsare non-toxic and well known to the body due totheir natural presence [18]. The addition of Ca andNa results in cleavage of P–O–P linkages due tothe creation of non-bonding oxygens (NBO). Evenwhen calcium ions are in contact with two NBO, alink with stronger effects on the network connec-tivity is created [19].

Calcium

Calcium (Ca) takes part in many biochemical reactionsand in every metabolic pathway there is a calcium-dependent step. It controls the mechanical stability ofcell walls and membranes and the filament tension inmany cells [36]. Intercellular Ca2+ level controls

ADVANCES IN APPLIED CERAMICS 3

processes like muscle contraction, transport processes,cell division and growth, enzyme activation and meta-bolic processes. Ca is intimately associated with foetaldevelopment and hormonal activities [38]. Calcium isan important component of mineralised biological tis-sues such as shells, teeth and bone (the largest reservoirof calcium in the body) and is typically expressed ascalcium salts, carbonates and phosphate-based biomin-erals. Also, important organelles like mitochondria andchloroplasts depend on a highly controlled calciumlevel. Calcium controls neuromuscular excitability,proper heart beating, blood clotting, and the degreeof hydration of the cytoplasm. Addition of calciuminto PBG results in favoured osteoblast proliferationand differentiation, ECM mineralisation and the acti-vation of Ca sensing receptors in osteoblast cells toincrease the expression of growth factors such asIGF-I or IGF-II [33].

In phosphate glass networks, calcium has twostructural functions, it can both modify the primaryglass structure and provide inter-chain cross-linking.In PGF specifically calcium ions provide the cross-link between non-bonding oxygens of the differentchains making the fibres more durable, given thatCa decreases degradation and improves the mechan-ical properties of the glass. Increasing calcium oxide(CaO) can reduce the tendency of crystallisation [2],however only to a certain level. Glasses with 35–40mol-% of CaO and low sodium level (<15 mol-%)are prone to crystalise [27]. CaO appears in almostall known phosphate glasses for biomedical appli-cations as one of the major components and the Caamount differs according to the application. Highlevels of CaO result in Ca/P ratios that are similarto that of the mineral phase of bone, Ca/P ratio isequal to 1.67. Binary calcium phosphate fibres are apopular group of materials which support boneingrowth [39].

Sodium

Sodium (Na) is an important element in the humanbody. Na plays many roles: it controls osmoticpressure in conjunction with K+ and Cl−, controlsthe electrolytic balance, membrane potential, and con-densation of polyelectrolytes. Na along with K takespart in passive diffusion, active transport and ionexchange across membranes. Sodium is also animportant component of gastric fluid [36]. Na2O isimportant for glass manufacturing because it is aneffective flux and reduces the viscosity of the glassmelt. However, Na2O reduces the resistance to chemi-cal attack and weakens the mechanical properties ofglasses [11]. According to Van Wazer’s reorganisationtheory monovalent oxide modifiers like Na2O disturbthe structure of P2O5 by breaking bridging oxygenbonds and forming non-bridging oxygens [40]. Onthe other hand, Na2O increases the thermal expansionof glass [41], while also increasing solubility and thetendency to crystallise [2].

Delivery of therapeutic ions – dopants

The ternary system ‘P2O5–CaO–Na2O’ has been widelyinvestigated to determine the correlation between com-position and cellular activity. However, to achieve bet-ter flexibility or durability, incorporation of aquaternary component is usually considered. Indeedsome interesting PGF contain five or more differentoxides to not only improve biocompatibility or mech-anical properties but also to increase the processingwindows [2].

Some of the well-known dopants are able to changethe biological features of phosphate glasses improving:cell attachment and proliferation and in the down-stream steps: tissue regeneration, surface properties ofthe material, degradation rate and dissolution rate.

Figure 2. Techniques for PGF manufacturing: (a) melt-drawing spinning process, (b) preform technique, (c) pulling from meltingsolution, adapted from Colquhoun and Tanner [32]. CopyRights CC BY 3.0. DOI:10.1088/1748-6041/11/1/014105.

4 A. LAPA ET AL.

The high dissolution rate of PBG and ion release cancause potential risk of allergic reaction or toxicity ofdopants. Still little is known about the function ofsome elements and especially about their safe doselimits; the same element may cause a positive effectin small amounts and become dangerous at higher con-centrations [42]. In recent years numerous researchactivities have taken place to find possible new appli-cations for PGF doped with different oxides, especiallyas scaffolds for tissue regeneration or as reinforcementof bone fixation devices [43,44].

Table 1 summarises the different elements assessedin the baseline ‘P2O5–CaO–Na2O’ compositions. Acommentary on each element follows in which theirrole in the human body and their impact on phosphateglass fibre properties are discussed.

Iron in PGF

Iron (Fe) is often used as a dopant in PGF. Iron playsan essential role in the human body by being respon-sible for a number of biological processes: Fe is acomponent of haemoglobin, takes part in cell div-ision and respiratory processes [67]. Iron oxide(Fe2O3) has a large impact on the properties of

phosphate glasses such as solubility or degradation,however in industry Fe2O3 has been used mostly asa colourant [68].

Fe increases Tg (glass transition) and Ts (temp-erature of softening), chemical durability, glass den-sity and decreases solubility or ion release [56,69].Total surface energy also decreased with increasingFe2O3 content. At low temperatures, iron increasesthe viscosity of the glass melt especially at higherphosphate levels, however, it is still the amount ofphosphate which retains the greatest influence onglass viscosity [70]. Biological properties of Fe2O3

have shown that PGF with 4 or 5 mol-% of Fe2O3

in a glass network provide better cell attachmentas well as proliferation and differentiation comparedto undoped fibres. However, the improved biocom-patibility of Fe-PGF is attributed to their enhanceddurability. Fe replaces P in P–O–P network and cre-ates strong cross-linking P–O–Fe units which alsoreduce the tendency to crystallise [69]. It is notclear if Fe(II) or Fe(III) is present in the network,nevertheless it has been proven that Fe(III) ismore likely to behave as a network former than asa network modifier [27].

The medical applications are bone fixation devices,dental application and nerve tissue regeneration. Fe-doped PGF were used with coupling agents to improvebone-ligament integration [30] and to treat traumascovering not only bone damage but also the surround-ing soft tissue. Moreover, Fe-PGF has been used toinvestigate the role of annealing in slowing down thedegradation of PGF by 50% [63].

As a scaffold, Fe-doped PGF were used for muscledelivery system to treat DuchenneMuscular Dystrophy[27]. To date the only effective treatment is muscletransplantation which delivers the normal gene into adiseased area, however the described procedure hastwo main disadvantages: risk of rejection and low sur-vival rate of implanted cells. Furthermore, the mobilityof injected myoblasts is limited [27]. Application of Fe-doped PGF is beneficial considering the predictabledissolution time and relative high solubility. Addition-ally, implantation of long fibres allows better cellattachment. Glasses with 50P2O5–(30, 35, 40)CaO–(20–x)Na2O–xFe2O3 (x = 1–5) (mol-%) compositionhave been proven to have good cell attachment andenhance proliferation and differentiation of muscleprecursor cells [27].

Magnesium in PGF

Next to Fe2O3, magnesium oxide (MgO) is most oftenused as a dopant in PGF, and similar to iron, mag-nesium (Mg) is a trace element in the human body.In contrast to Fe2O3, the main role of MgO is toimprove the biological properties of PBG. In glass tech-nology magnesium oxide is mostly used as a colourant

Table 1. Summary of studies on phosphate glass fibres withdifferent compositions intended for biomedical applications.

Ternary Phosphate Glass Fibres Ref.

Fe (63.3–56.9)P2O5–(32.7–26.2)CaO–(3.6–16.9)Fe2O3

[45]

Al andZn

69.2P2O5–21.9Al2O3–15.2ZnO [46]

basics P2O5–Na2O–CaO [47]Quaternary Phosphate Glass FibresMg 40P2O5–20Na2O–16CaO–24MgO [28,48,49]Fe 50P2O5–5Na2O–40CaO–5Fe2O3 [17,23,50–

52]50P2O5–1Na2O–46CaO–3Fe2O3 [16]50P2O5–(20-15)Na2O–30CaO–(0-5)Fe2O3 [18]40P2O5–16Na2O–16CaO–(1–5)Fe2O3 [53]50P2O5–Na2O–(30-40)CaO–(1-5)Fe2O3 [27]50P2O5–(1–4)Na2O–46CaO–(0–3)Fe2O3 [30]50P2O5–(15–17)Na2O–30CaO–(3-5)Fe2O3 [24]

Cu 50P2O5–(20–10)Na2O–30CaO–(0–10)CuO [54]Si 51.04P2O5–25.51Na2O–21.42CaO–2.03SiO2 [55]Al 69.2P2O5–21.9Al2O3–15.2ZnO [46]

60P2O5–20Na2O–(0–20)Al2O3–(0–20)Fe2O3 [56]67.5P2O5–15ZnO–(0–17.5)Al2O3–(0–17.5)Fe2O3

Quinary Phosphate Glass FibresMg andFe

40P2O5–16Na2O–24MgO–16CaO–4Fe2O3 [43,57–61]45P2O5–10Na2O–16CaO–24MgO–5Fe2O3 [62]45P2O5–11Na2O–16CaO–24MgO–4Fe2O3 [31]

Mg andTi

35P2O5–22.5Na2O–21.5CaO–9.5MgO–5.5TiO2 [44]

Fe andZn

54P2O5–2.5Na2O–27CaO–12ZnO–4.5Fe2O3 [63]

Others compositionsMg Fe B 45P2O5–10Na2O–16CaO–24MgO–5B2O3–3

Fe2O3,45P2O5–10Na2O–16CaO–24MgO–5B2O3,45P2O5–17Na2O–16CaO–24MgO–3Fe2O3

[64]

48P2O5–1Na2O–14CaO–(25–x)MgO–12B2O3–xFe2O3 (x = 6, 8, 10)

[65]

45P2O5–5Na2O–(29–x)CaO–16MgO–5B2O3–xFe2O3 (x = 5, 8, 11)

[66]

Mg Si TiK

50P2O5–9Na2O–30CaO–3MgO–3SiO2–2.5K2O–2.5TiO2

[26,29]

ADVANCES IN APPLIED CERAMICS 5

(giving grey colour), moreover MgO, like CaO, canlower the annealing point of doped glasses [68].

Seventy-five per cent of magnesium in the humanbody resides in bone but it is also present in skeletalmuscle and soft tissues. Indeed, most Mg-dependentfunctions are related with bone tissues: stimulatingnew bone formation and increasing bone cell adhesionand stability [33,56]. Mg increases alkaline phosphatase(ALP) activity and short-term oral magnesium sup-plementation can minimise bone turnover markers inyoung adult males and post-menopausal osteoporoticwomen [42]. Moreover, Mg plays numerous importantroles in cell functions: stabilisation of lipid membranes,nucleic acids and ribosomes [71] chelation of anions toprevent them taking part in hydrolysis or assistingchemical reactions; structure stabilisation and main-taining the electrical potential of the cell membranesof neuromuscular cells. Magnesium, together with cal-cium, is present in membranes where it provides across-linking activity for carboxylated and phosphory-lated anionic polymers. Finally, Mg takes part in trans-port processes and ion pumping processes in cells.

The structural and biological properties of MgO-doped PBG were exhaustively described by Ahmedet al. [72]. Glasses were doped with 10, 20 and 30mol-% MgO; increasing MgO content results in linearincreases in Tg, cross-link density and the chemicaldurability. Degradation of these glasses decreaseswith increasing MgO content as monovalent Na+ issubstituted by divalent cation Mg2+ in the glass net-work. Glasses with 30% MgO tended to crystallise onthe surface upon cooling to room temperature. How-ever, rapid changes in coordination number of Mg2+

ions have an anomalous effect on the physical proper-ties of phosphate glasses [69]. Biological tests haveshown higher osteoblast activity for glasses with 20–30 mol-% MgO, however no apparent relationshipbetween glass composition and cell attachment hasbeen observed in correlation to MgO content. PGFwith MgO have been used for reinforcement of bonefixation devices, in nerve tissue regeneration and asdrug delivery systems [29].

Copper in PGF

Copper oxide (CuO) has been used in glass technologyfor many years. The antibacterial properties of copperhave also been well exploited since ancient times as evi-denced by its use to sterilise water [73]. Of more cur-rent relevance, CuO influences the properties of PBG,in particular, the degradation rate or ion release.

Cu is a biologically important element. Significantamounts of cellular copper are found in human endo-thelial cells when undergoing angiogenesis, promotingsynergic stimulation effects on angiogenesis whenassociated with angiogenic growth factor FGF-2. Custimulates proliferation of human endothelial cells

and induces higher differentiation of mesenchymalstem cells towards the osteogenic lineage [33]. Theimportant oxidase enzyme ceruloplasmin, present inplasma and used to transport proteins, requires Cuwhere it helps to metabolise iron. Deficiency of copperresults in iron overload in the tissues of the brain andliver, however high doses of copper may result in itsaccumulation in the liver [73]. Cu is a cofactor forsuperoxide dismutase (enzyme catalyses O2

- into O2

or H2O2) and lysyl oxidase (critical role in biogenesisof connective tissue). The GHK-Cu complex increasesmessenger RNA production of various extracellularmatrices such as collagen, elastin, proteoglycan or gly-cosaminoglycans in fibroblasts. Inorganic copper wasused in implants and research proved that 56 ng ofcopper sulphate per implant achieves a positive effecton blood vessel ingrowth [42,73]. Copper is essentialfor cross-linking of collagen and elastin which isimportant to form a strong, flexible connective tissuein skin and bone and also plays an important role inbone resorption. It has been proven that osteoclastsproduce Cu/Zn superoxide dismutase (SOD), adecrease of Cu/Zn SOD activity due to inadequate cop-per levels leads to increasing bone resorption [73].

Cu-PGF were used to obtain materials for woundhealing application. PGF with 10 mol-% of CuO haveshown antibacterial properties by killing the opportu-nistic pathogen Staphylococcus epidermidis [54].Many PBG with antibacterial dopants like Ag, Zn,Cu, Ga, etc. [74–76] have been reported howeveronly one example of incorporation of copper intoPGF is available [54].

Research by Knowles et al. has proven that additionof CuO increases the Tg of the glass, as well as Ts, hard-ness and the chemical durability. In the glass, instead ofP–O–Na bonds, P–O–Cu bonds were formed due to thehigher electronegativity of copper ions vs. sodium ions.Substitution of Cu results in an increase in cross-linkdensity and a decrease in degradation rate [54].

Boron in PGF

Boron oxide (B2O3) is one of the network-formeroxides, however, it is also often used as a flux. Additionof boron (B) improves both chemical resistance andmechanical properties of glasses. Glasses containingB2O3 are characterised by low thermal expansion andresistance of thermal shock [41]. It has been shownthat crystallisation temperature increases with increas-ing B2O3 content [73,77].

In organisms, B stimulates RNA synthesis in fibro-blast cells, stimulates bone formation, and is respon-sible for expression of RUNX2, a growth factor forosteoblastic differentiation and bone formation [78].Boron works together with calcium and is present inthe bone and neural systems. One of boron’s mainroles is to metabolise the major minerals: calcium,

6 A. LAPA ET AL.

magnesium and phosphates. Deficiency causes areduction in the urinary excretion of Ca, Mg and P,elevates the serum concentration of estradiol-17β andtestosterone and can even cause calcium loss / bonedemineralisation in postmenstrual women. Boric acidreduces the time required in intensive wound care by66% due to an ability to activate the key enzymesinvolved in fibroblast formation which improves extra-cellular-matrix turnover [78]. B significantly improveswound healing, an anti-inflammatory effect fromboron was observed as a result of inhibition of the oxi-dative burst by leukocytes and excessive activity byneutrophils [78]. Addition of borate improves thebioactivity of PBG by promoting hydroxyl group for-mation at the surface of glasses and some borate glasseshave been proven to bond to bone at levels comparableto Bioglass 45S5 [77].

Addition of 5 mol-% B2O3 into PGF with compo-sition: 45P2O5–16CaO–24MgO–5Na2O (mol-%) sig-nificantly increases tensile strength (50%) andmodulus (11%). However, similar increases werereported from a synergistic effect of adding 5 mol-%of B2O3 and 3 mol-% of Fe2O3. A 22% decrease in thedissolution rate was observed by adding either 5 mol-% of B2O3 or 3 mol-% Fe2O3 while in glasses dopedwith both B2O3 and Fe2O3 there was only an 11%decrease in dissolution rate. Both B and Fe-dopedPGF show similar degradation rate of 20 µm diameterfibre samples. Despite this B2O3 significantly improvesthe mechanical properties of the fibres, whereas theglasseswith iron have shownbetter biological propertieson human osteosarcoma [64]. Lower biocompatibilityof high-boron phosphate glasses is associated withextensive release of B3+ ions [69].

Strontium in PGF

Strontium (Sr) is an alkaline earth metal which hasfound application in osteoporosis treatment [79]. Stron-tium reduces bone resorption, stimulates bone for-mation and increases replication of preosteoblasticcells [79,80]. Moreover, a correlation between anincrease in the amount of Sr in bone and compressivestrength has been found [81]. There are several simi-larities between calcium and strontium: they have simi-lar metabolic pathways by gastrointestinal tract(absorption) and the urinary systems (extraction) andboth are concentrated in the bone [80]. However, highsimilaritiesmay lead to complication due to replacementof calcium with strontium in bone [79]. Nevertheless,many soluble phosphate glasses have been proposed asa system of controlled strontium release [79,80,82,83].

Several studies have shown the influence of stron-tium on PBG. The substitution of calcium with stron-tium results in increased glass density and molarvolume due to the larger ionic radius of Sr2+ comparedto Ca2+. Weaker Sr–O bonds lead to a slight decrease in

Tg while Tm was significantly lower [79]. High amountsof Sr decrease the processing window and can causeproblems with fibre drawing [79] however accordingto Massera et al., glasses doped with 20 mol-% of Srwere characterised with good stability and possibilityto draw fibres [84].

Studies on 40P2O5–25CaO–5Na2O–(30-x)MgO–xSrO [mol-%] phosphate glasses have shown animproved cell proliferation (1% of Sr), hMSC osteo-genic differentiation (5%) and an increase in earlyosteogenic markers such as COL1 and RUNX andlater markers ALP and OC [83]. Based on this evalu-ation, the optimal Sr concentration in PBG has beenset as 5 mol-% [83].

PGF doped with strontium were used to produceporous scaffolds for bone tissue regeneration as pro-posed by Zheng et al. [85,86].

Potassium in PGF

Sodium and potassium oxides (Na2O, K2O) impartsimilar properties to glassy materials being powerfulfluxing (melting) alkaline materials. However, repla-cing with sodium and potassium results in melts ofhigher viscosity and lower thermal expansion [68].

Addition of mixed alkali oxides to glasses results inhigher durability and electrical resistance [41]. Increas-ing the amount of alkali ions in PBG is known todecrease connectivity of the glass structure by creatingnon-bridging oxygens, hence increasing the thermalexpansion coefficient and solubility [56].

Potassium is an essential element for human health.The main roles for K are regulation of acid–base bal-ance, energy metabolism, controlling blood pressure,membrane transport, distribution of fluid within thebody, transmission of nerve impulses and maintainingcardiac function [87]. K controls the electric potentialof cell membranes as one of the outer membraneions. It also takes part in regulating osmotic balance.

K2O has been used to produce PGF for nerve tissueregeneration. PGF labelled as TiPS 2.5 contained50P2O5–30CaO–12Na2O–3SiO2–2.5K2O–2.5TiO2

(mol-%). PGF were suitable for glial cells and axonalgrowth. Neonatal olfactory bulb ensheathing cells(NOBEC) were well spread on the fibre surface andactive proliferation was also observed. Some of thecells presented cytoplasmic processes extending alongthe fibres. TiPS 2.5 were also used to test Dorsal RootGanglia neurons which showed a pseudo-unipolarmorphology [26]. Moreover, K2O was used to obtainhollow glass fibres for a controlled release system [29].

Silica in PGF

Silicon oxide (SiO2) is mainly used as a network-for-mer. Silica-based bioactive glasses are being extensivelystudied for their potential to bond to hard and soft [88]

ADVANCES IN APPLIED CERAMICS 7

tissue and their ability to release biologically active ions[33]. A particular silica-based glass called Bioglass 45S5has great biological potential [89]. Silica-based glassesproduced by both melt-quench and sol-gel are less sol-uble than the PBG described in this review.

Silicon (Si) is also an important element in humanhealth, it is essential for metabolic processes and for-mation and calcification of bone tissue [33]. Dietaryintake of Si increases bone mineral density, while Si–O in an aqueous environment induces HA precipi-tation and Si(OH)4 stimulates collagen I formationand osteoblastic differentiation [33]. Si along with Caplays an important role in the early stages of calcifica-tion [42]. Silica can be used as a dopant to modify theproperties of PBG.

Glasses with composition 50P2O5–40CaO–5SiO2–5Fe2O3 (mol-%) degrade faster than those without silica.Si–O–P bonds are more sensitive to hydrolytic activitybecause inclusion of Si acts to disconnect the networkof phosphate glasses. It also results in faster ion releasein water in line with the dissolution rate [42,90].

PGF containing Si have been used as materials forbone fixation devices, in soft tissue regeneration, inmuscle delivery systems and scaffolds for nerve tissueregeneration [90].

Titanium in PGF

Titanium (Ti) is a popular and widely investigatedelement in biomaterials [91]. Titanium alloys are themost widely used metals in orthopaedic implants. Tita-nium oxide (TiO2) has been incorporated into differentglasses, both silica and phosphate types, due to theexpected improvement of the biological response.However, TiO2 also has other effects on glass proper-ties, Ti: improves the resistance to acid attack, inhibitscrystallisation, decreases solubility and increases theprocessing window [2]. Owing to a high charge-to-size ratio of Ti4+, titanium has strong ionic strength.Phosphate glasses with a lower content of P2O5 andshorter chains were shown to crystallise more easily,while an addition of Ti4+ with strong ionic cross-link-ing prevents it [2].

The viscosity of glass melts increases with TiO2 con-tent [26] due to the formation of covalent Ti–O–Pbonds or ionic cross-links between phosphate chains.Ti stabilises glass networks, increases glass character-istic temperatures, increases density and prevents low-ering of pH during dissolution [26].

The lower solubility of Ti-doped PBG improves celladhesion which results in superior proliferation assayswith murine pre-osteoblast cells [44]. Titanium hasbeen used in PGF (TiPS) for nerve tissue regenerationand muscle delivery systems. Additionally, Ti is used ininvert PGF with composition 35P2O5–27.5CaO–22.5Na2O–9.5MgO–5.5TiO2 (mol-%) as a bone regen-eration material [44].

Aluminium in PGF

In spite of the fact that aluminium (Al) cannot form aglass alone, Al takes part in the glass network as anintermediate oxide [68]. Aluminium increases chemi-cal durability has no effect on thermal expansioncoefficient and induces a lower dissolution rate[28,56]. Aluminium can work as a network formerby creating AlO4 units which can bond to P=Obonds, causing double bond removal (reduction)with the ‘O’ changing to a bridging oxygen. Additionof Al2O3 into a glass network and substituting sodiumwith alumina can increase the strength of PBG [56].Aluminium is essential for plant development, e.g.club moss, hydrangea and tea plant but there is nodefinite general biological role in humans or higheranimals [92].

Al-doped PGF with composition 62.9P2O5–21.9Al2O3–15.2ZnO (mol-%) were used as a muscledelivery system [46]. Moreover, different fibres con-taining Al2O3 have been considered as reinforcementfor medical fixation devices [56].

Zinc in PGF

In traditional glass manufacturing, zinc (Zn) has beenused as a flux [68]. Recent research has proven that zincis beneficial for osteoblast attachment but only up tocertain levels after which it becomes toxic for cells[93]. Wang et al. [94] proved that zinc concentrationwithin range from 0 to 0.59 ± 0.03 mg−1 was confirmedto promote bone growth in vivo.

Zinc has many advantages: it shows an anti-inflam-matory effect and stimulates bone formation in vitro byactivation of protein synthesis in osteoblasts andincreased ATPase activity. It regulates transcriptionof osteoblast differentiation genes, collagen I, ALP,osteopontin and osteocalcin [33]. Zn plays a role inbone healing and the absence of it may cause blindness.Zinc is the most common trace element metal ion pre-sent in the cytoplasm of advanced aerobic cells. Thestructural role of zinc is to stabilise filamentary, kera-tin-like structures for the organisation of chromosomes[36].

Mechanical tests on PGF have shown doubling ofthe tensile strength values (from range between 2.8–4.2 GPa and 4.2–7.2 GPa) when substituting Na withZn [56]. Also, a significant decrease in the degradationrate has been observed. Zn-doped PGF were used inregeneration of craniofacial muscle tissue [46] andreinforcing materials for bone fixation devices [27].

Applications of phosphate glass fibres

PGF are used both for hard and soft tissue regener-ation, as a scaffold, wound dressing or reinforcementfor bone fixation devices. The application is strongly

8 A. LAPA ET AL.

correlated with the glass composition. Table 2 sum-marises the use of PGF for medical applications.

PGF for hard tissue regeneration

In bone tissue regeneration applications, bioactiveglasses and ceramic materials are frequently studiedbecause of their interesting ability to bond to bone –their bioactivity [97]. PBG are not an exception, how-ever PGF, because of their geometrical characteristicshave been mainly studied for bone fixation devices.Numerous articles describe the advantages of usingPGF in combination with resorbable polymers such asPLA, PCL or PLGA [17,43,44,50,51,55,58,59,62,90,98–101] The aim is to obtain bone fixation devices with amodulus similar to that of natural bone, which also dis-appears completely after the healing process is com-pleted. This disappearance will necessarily be

associated with a decrease in mechanical propertiesthat will be offset by the presence of newly formedbone. PLA, PCL and PLGA have much lower mechan-ical properties than cortical or cancellous bone so rein-forcing PGF are used to improve the mechanicalperformance of such polymers. The measured valuesfor polymers are as follows: PLA tensile modulus4.4 GPa; PCL tensile strength 190 MPa; PGA tensilestrength 57 MPa, tensile modulus 6.5 GPa [102], whilemechanical properties of cortical bone reaches valuesof 50–150 MPa and 7–30 GPa, for flexure strengthand elastic modulus, respectively [32]. Compositesobtained from resorbable polymers and PGF allow thecreation of materials more suitable for bone application[103]. Bioresorbable screws, rods or nails are examplesof PGF-based composites for bone regeneration[27,57,90]. Such components are also a convenientalternative for metallic implants which commonly

Table 2. Summary of PGF according to their medical applications. PGF have been used both for hard and soft tissue regenerationdepending on their composition.Type of tissue Application Fibre composition (mol-%) Key results

Hard tissue Reinforcement 40P2O5–16Na2O–16CaO–24MgO–4Fe2O3 Investigation of degradable composite for bone fixation [57] devicesas screw [25] and rods [43] and their properties [60], improvementof bone-to-implant bonding [61]

45P2O5–13Na2O–16CaO–24MgO–2Fe2O3 Improved method of manufacturing fibre-polymer composites [95]45P2O5–10Na2O–16CaO–24MgO–5B2O3–3Fe2O3

Fe and B improved mechanical properties of the fibres [62] Fibresdoped with Fe showed better biological response than thosecontaining B [64]45P2O5–10Na2O–16CaO–24MgO–5B2O3

45P2O5–17Na2O–16CaO–24MgO–3Fe2O3

50P2O5–5Na2O–40CaO–5Fe2O3 PGF/PLA composite as bone fixation devices, influence of gammasterilisation [17,50,51]

35P2O5–22.5Na2O–21.5CaO–9.5MgO–5.5TiO2 Addition of Ti stabilises glass structure, decreases solubility andimproves cell attachment, mechanical properties in range ofcortical bone [44]

(63.7–56.9)P2O5–(32.7–26.2)CaO–(3.6–16.9)Fe2O3

Improved mechanical properties due to presence of Fe [45]

50P2O5–40CaO–(0–10)SiO2–(0–10)Fe2O3 Fe and Si decreased dissolution rate of PGF which in combinationwith PLA gives composite with long-term application andcytocompatible with bone cells [90]

51.04P2O5–25.51Na2O–21.42CaO–2.03SiO2 Bone fixation devices with CaCO3 to control pH in order to avoidfaster degradation or inflammatory reaction in vivo [55]

40P2O5–20Na2O–16CaO–24MgO Understanding of the process of degradation, its non-linear characterand the influence of annealing [28]

54P2O5–2.5Na2O–27CaO–12ZnO–4.5Fe2O3 High-temperature annealing decreases degradation and is the mostsuitable for fibres for bone fixation devices application [63]

40P2O5–10Na2O–20CaO–10B2O3–10K2O–5MgO–5SrO

Porous scaffold based on PGF with mechanical properties similar tocancellous bone [96]

Bone implants 40P2O5–16Na2O–16CaO–24MgO–4Fe2O3 Studies on improving bonding between PGF and polymer matrixwhich causes an increase in mechanical properties and decreasedissolution [58, 59]

50P2O5 (1–4)Na2O–46CaO–(0–3)Fe2O3 PGF with high calcium content and doped with Fe supportattachment and proliferation of both osteoblast and fibroblastwhat makes them interesting materials for bone and ligamentregeneration in complex traumas and injuries [30]

45P2O5–16CaO–24MgO–11Na2O–4Fe2O3 Strong bonding between PGF and polymer matrix using [31]Soft tissue Muscle 69.2P2O5–21.9Al2O3–15.2ZnO PGF has been used as a scaffold for craniofacial skeletal muscle

supporting cell attachment [46]50P2O5–Na2O–(30–40)CaO–(1–5)Fe2O3 PGF has been used to deliver muscle precursor cells as an alternative

treatment for Duchenne muscular dystrophy [27]Skin 50P2O5–Na2O–30CaO–(1–10)CuO PGF for wound healing application with antibacterial properties due

to presence of Cu [54]Nerve 50P2O5–5Na2O–40CaO–5Fe2O3 Collagen-PGF scaffold support direction growth of neurites [23] and

were successfully implanted in an animal model, showing positiveresult in spinal cord regeneration [52]

50P2O5–9Na2O–30CaO–3MgO–3SiO2–(0-5)K2O–(0–5)TiO2

Good adhesion of gliac cells on the PGF surface and neuronsextended long axons along the fibre axis direction [26]

Delivery system 50P2O5–9Na2O–30CaO–3MgO–3SiO2–(0-5)K2O–(0-5)TiO2

Hollow PGF has shown capillary action and have potential to be usedas drug delivery system [29]

Hard-soft tissueinterface

50P2O5–1Na2O–46CaO–3Fe2O3 three-dimensional scaffold supports early tissue formation of bone,ligament and tendon (bioreactor) [16]

ADVANCES IN APPLIED CERAMICS 9

have elastic moduli which are too high. Mismatch inelastic modulus may cause stress shielding in the sur-rounding bone and absence of mechanical stimulation[32], which results in a weakening of the bone [104].The most common fibres used in these applicationsare Fe-doped PGF and B-doped PGF. Those dopantshave been shown to improve mechanical propertiesand to decrease solubility of PGF. The most suitableduration for composites for bone application beforecomplete dissolution should be around 6–8 weeks [32].

Novajra et al. [21] and Zheng et al. [86] suggestedusing PGF-based 3D porous scaffolds for bone regener-ation. Both systems are promising materials for boneregeneration due to their suitable mechanical proper-ties (yield stress 0.38 and modulus 2.84 MPa) similarto cancellous and trabecular bone (compressivestrengths of 0.15 MPa and 2–3.5 MPa respectively),good cell response and stimulation of hydroxyapatiteformation. Chen et al. proposed a modification ofstainless steel bone implants by embedding a shortPGF on their surface using electrophoretic deposition(EPD). Addition of fibres is expected to improvebone-to-implant bonding as it enhances proliferationand migration of MC3T3-E1 cells [61].

PGF for soft tissue regeneration

PGF are frequently studied for use in soft tissue regen-eration, especially in nerve tissue regeneration, woundhealing and muscle delivery systems. However, com-pared to their application as hard tissue regenerationmaterials, their use in soft tissue healing is not as wide-spread. Nonetheless, the unique properties of PGF havebeen appreciated and are slowly receiving recognitionalso in soft tissue regeneration.

An especially interesting and promising applicationof PGF is in nerve regeneration [23,25,52]. Reported byJoo et al. for the first time, treatment with PGF resultedin full regeneration after spinal cord injury in a ratmodel. 18 µm fibres with composition 50P2O5–40CaO–5Na2O–5Fe2O3 (mol-%) were used to produce3D collagen scaffolds which were implanted into theanimal transected spinal cords. High levels of Ca andFe in the glasses enabled the preparation of less solublefibres which better supported neuronal growth. After12 weeks, the locomotion ability was improved andthe result for PGF-collagen scaffolds was better thanfor PGF-free ones. The positive impact of PGF onneuronal growth was confirmed due to the capacityof aligned PGF to provide directional guidance for out-growing axons [52].

50P2O5–30CaO–9Na2O–3SiO2–3MgO–(5–x)K2O–xTiO2 (mol-%) fibres were used for nerve regenerationand it was proven that neurites outgrew along thedirection of the fibre axis. The fibre surfaces providedsupport for cell attachment and proliferation due tohigher stabilisation (lower solubility) and stiffness.

Additionally, the tendency for growth along the fibreaxis increased with decreasing fibre diameter [26].Similar studies were performed on a peripheral nerveinjury which can heal unaided but only in a very lim-ited way [23]. The fibre/collagen scaffolds were manu-factured using 50P2O5–40CaO–5Na2O–5Fe2O3 (mol-%) glass fibres. To investigate the influence of thefibres on nerve regeneration an animal model (12-week adult rats) was used. After 12 weeks, the resultsfor collagen (Coll) and PGF/Coll were similar howeverthe first sign of regeneration appeared 2 weeks earlierfor scaffolds with fibres (6 instead of 8 weeks) [23].

PGF for both hard and soft tissue regeneration

Properties to support both soft and hard tissue regen-eration are especially important in applications whereboth bone and ligament regeneration must be sup-ported in the tissue interface regeneration filed. Manytraumas cover not only bone damage but also the sur-rounding soft tissue [30]. For example, three-dimen-sional scaffold using PGF was made to produce soft-hard tissue integration at the bone-ligament interface.50P2O5–46CaO–(4–1)Na2O–(1–3)Fe2O3 (mol-%)fibres were produced and tested with HOB and HOFcells. During these studies, it was proven that 3% ofFe2O3 supports cell attachment and proliferation.Cells of both types were flat and showed spread mor-phology which suggested very good attachment andintegration with the material’s surface [30].

Other biomedical applications of PGF

Hollow 50P2O5–30CaO–9Na2O–3SiO2–3MgO–2.5K2O–2.5TiO2 (mol-%) PGF were used as a con-trolled release system that offered an alternative fororal drug administration to avoid liver damage causedby drugs absorbed through the gastrointestinal tract.Such fibres act as capillaries and are able to transportsolutions and release them from extremities (70%after 5 h and 100% after 24 h). Such a system may beespecially interesting to transport biologically activemolecules [29].

A similar system has been investigated using50P2O5–30CaO–(17–15)Na2O–(3–5)Fe2O3 (mol-%)PGF with diameter 32 ± 7 µm. PGF have been fabri-cated which degrade upon soaking to spontaneouslyform capillary channels. The process seems to startafter 1 week when cracks appeared and after 3 monthsfibres were replaced by hollow tubes that formed overthe following 6 to 18 months. Incubation in deionisedwater caused depolymerisation of the glass networkdue to a combination of surface hydration and internalhydrolysis reactions. Another explanation of theobserved behaviour is the difference in chain strengthbetween the outer and the core part of the fibres. Therapid cooling during manufacturing of fibres tends to

10 A. LAPA ET AL.

create stronger bonds on the outer layer. Such fibreshave potential application as controlled drug deliverysystems. Moreover, PGF showed congruent degra-dation with zero order release which makes them suit-able materials for antibacterial applications in theirown right, as potential sources of antibacterial elementssuch as Ag or Cu [24].

A unique application of soluble 50P2O5–30CaO–20Na2O (mol-%) PGF has been reported by Alshomeret al. [105] who used them as a sacrificial material forscaffolds for tendon regeneration. Toproduce a patternedsurface, PGFhavebeenput on the interface of liquid poly-merPolyhedralOligomeric SilsesquioxanePoly (Carbon-ate-urea)Urethane (POSS-PCU). The scaffoldwas placedin deionised water until complete dissolution of the PGFand demonstrated good cell response [105].

Summary

PGF are interesting materials with a wide range ofmedical applications which can be used in contactwith both hard and soft tissues. PGF offer useful vari-ation in shape (high aspect ratio) which hold greatpromise in medical applications. Modification of fibrecomposition can be employed to enhance the mechan-ical properties of PGF, used for example in bonefixation devices, or increase their solubility for appli-cation as drug delivery systems. Moreover, addition ofcertain ions can improve the biological response andexpand the possible applications: nerve tissue regener-ation, wound healing, muscle cell delivery system,bone regeneration and bone-ligament regenerationare all examples which are highlighted and discussed.Owing to their potential high solubility, PGF can beconsidered as a source of therapeutic ions which canbe beneficial for cells, but in higher doses may bringabout undesirable effects. Appropriate design of thechemical and physical properties of PGF requires aninformed awareness of the possible impacts upon apatient’s body. This information is critically importantto mitigate the hazardous effects of certain metallic ionsin order to broaden the medical applications of PGF.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

HyMedPoly received funding from the European Union’sHorizon 2020 research and innovation programme underthe Marie Sklodowska-Curie grant agreement No 643050.

ORCID

Agata Lapa http://orcid.org/0000-0002-2130-9643Mark Cresswell http://orcid.org/0000-0002-5636-3797Aldo R. Boccaccini http://orcid.org/0000-0002-7377-2955

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