Progress of supercritical fluid technology in polymerization and its applications in biomedical engineering

Progress in Polymer Science 98 (2019) 101161

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Progress in Polymer Science journal homepage: www.elsevier.com/locate/ppolysci

Progress of supercritical fluid technology in polymerization and its applications in biomedical engineering Wen-Chyan Tsai, Yadong Wang ∗ Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, 14850, United States

a r t i c l e

i n f o

Article history: Received 12 April 2019 Received in revised form 2 August 2019 Accepted 13 September 2019 Available online 16 September 2019 Keywords: Supercritical fluid Lipase Biodegradable polyester Biomedical engineering Microcapsule Microcellular scaffold

a b s t r a c t Supercritical fluid technology has emerged as a cost-effective and low-hazard alternative to solvent-based methodologies in polymer synthesis, pharmaceutical science, and related biomedical applications. In this review, we first briefly describe the distinctive features of a supercritical fluid, biodegradable polyesters, and lipases. We will then cover the latest progress of supercritical fluid technology in polymerization. Lipase-catalyzed polymerization in supercritical carbon dioxide (SC−CO2 ) will be the focus of the synthesis section. The last section presents the biomedical applications employing SC−CO2 polymerization, including microcapsule formation for drug delivery, microcellular scaffold fabrication, and SC−CO2 assisted processes for polymer-based treatments, such as surface functionalization, aerogel formation, and fine particle formation. Each topic is illustrated with the most successful examples. Understanding the current progress in SC−CO2 polymerization is an essential step to facilitate the exploration with this green technology in new research frontiers. © 2019 Elsevier B.V. All rights reserved.

Contents 1.

2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.1. A supercritical fluid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.2. Biodegradable polyesters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 1.3. Lipases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Supercritical fluid technology in polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.1. Polycondensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 2.2. Ring opening polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.3. Enzymatic polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.3.1. Lipases from different sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.3.2. Mechanism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 2.3.3. Effects of operating parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Abbreviations: AA, acrylic acid; AB, ammonium bicarbonate; AIBN, 2,20-Azobisisobutyronitrile; ASES, aerosol solvent extraction system; AUL, absorption under load; C6, coumarin-6; CALB, Candida antarctica lipase B; coQ10 , coenzyme Q10 ; CRL, Candida rugosa lipase; DDMAT, 2(Dodecylthiocarbonothioylthio)-2-methylpropionic acid; DELOS, depressurization of an expanded liquid organic solution; GF, growth factors; DTBP, Di-tert-butyl Peroxide; EGDMA, ethylene glycol dimethacrylate; hASC, human adipose-derived stem cell; HEMA, 2-hydroxyethyl methacrylate; HFP, hexafluoropropylene; HLB, hydrophilic-lipophilic balance; MCF, mesocellular silica foam; MMA, methyl methacrylate; MPEG, methoxy polyethylene glycol; MSC, mesenchymal stem cells; MT, 17␣-methyltestosterone; NaOH, sodium hydroxide; NIPA, N-isopropyl acrylamide; NVP, N-vinyl-2-pyrrolidone; Pc , critical pressure; PAA, poly(acrylic acid); PBP, perfluorobutyryl peroxide; PCA, precipitation with compressed anti-solvent; PCL, polycaprolactone; PCL–HA, polycaprolactone–hydroxyapatite; PDI (Ð), polydispersity index; PDLLA, poly(D,L-lactic acid); PEG, polyethylene glycol; PET, polyethylene terephthalate; PGSS, particles from gas saturated solutions; PHB, poly(␤-hydroxybutyrate); PL, platelet lysate; PLA, polylactic acid; PLDO, poly(L-lactide-co-p-dioxanone); PLLA, poly(L-lactide); PMDOP, poly(2-methylene-1,3-dioxepane); PMMA, polymethyl methacrylate; PNIPAAm, poly(N-isop ropylacrylamide); Pro3 -TL, proline-replaced temporin L analogue; pSNP, polymer-grafted silica nanoparticle; PVAc, poly(vinyl acetate); PVDF, polyvinylidene fluoride; RAFT, peversible addition-fragmentation chain transfer; RESS, rapid expansion of a supercritical solution; ROP, ring opening polymerization; SAS, supercritical antisolvent; SCF, supercritical fluid; SC−CO2 , supercritical carbon dioxide; SEE, supercritical emulsion extraction; SEM, scanning electron microscopy; Sn(Oct)2 , stannous 2-ethyl hexanoate; Tc , critical temperature; Tg , glass transition temperature; Tm , melting temperature; TBTGA, S-thiobenzoyl thioglycolic acid; VF2, vinylidene fluoride. ∗ Corresponding author. E-mail address: [email protected] (Y. Wang). https://doi.org/10.1016/j.progpolymsci.2019.101161 0079-6700/© 2019 Elsevier B.V. All rights reserved.

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4. 5.

2.3.4. Examples for enzymatic polymerization in SC−CO2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.4. Homogeneous polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.5. Precipitation polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 2.6. Dispersion polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.7. Emulsion polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 2.8. Reversible addition-fragmentation chain transfer (RAFT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 SCF polymerization in related biomedical applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1. Microcapsule generation for drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1.1. Lipase-catalyzed polycondensation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1.2. Dispersion polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 3.1.3. Precipitation polymerization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2. Fabrication of microcellular scaffolds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2.1. SC−CO2 foaming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 3.2.2. Phase inversion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 3.3. The SC−CO2 -assisted processes for polymer synthesis and applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3.1. Impregnation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3.2. The RESS and SAS processes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3.3. Aerogel formation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 3.3.4. Supercritical emulsion extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.3.5. Purification and sterilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Trends in supercritical fluid technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

1. Introduction 1.1. A supercritical fluid Growing demands for sophisticated systems of drug delivery and tissue engineering drive the development of polymer syntheses using cost-effective and nontoxic processes [1,2]. Polymer synthesis using supercritical fluid technology can reduce or eliminate organic solvent usage and avoid harsh operating conditions, which commonly exist in conventional techniques of polymerization. A supercritical fluid (SCF) is defined as a substance possesses only a homogeneous phase above its critical temperature and pressure where the vapor/liquid boundary disappears within the SCF area. As presented in Table 1, a SCF combines gas-like properties of low viscosity and high diffusivity and liquid-like properties of solvation power and density [3,4]. Low fluid viscosity accelerates the chemical reaction kinetics in a SCF medium. A solute’s solubility in a SCF is a function of the fluid density, which can be adjusted by changing operating pressure and temperature in the supercritical region [5,6]. For a SCF, no surface tension exists in the homogenous fluid phase, due to the absence of a vapor/liquid interface in the supercritical state. Among different SCFs, supercritical carbon dioxide (SC−CO2 ) is commonly employed because of its nontoxicity, economic cost, inertness, and nonflammability. Its low critical temperature (Tc ) of 31.4 ◦ C can protect heat-labile compounds from thermal degradation. With medium critical pressure (Pc ) of 7.38 Mpa, operating cost and risk would be significantly reduced. CO2 is readily available as an industrial commodity and easily recycled after use. In the past two decades, interest in the use of SC−CO2 as a reaction medium has increased significantly. SC−CO2 has been exploited as a solvent for extractions of functional compounds [7–10], fine particle formation [11–13], microencapsulation [3,14,15], and enzymatic reactions [16–18]. Solubility determination of the targeted compounds in SC−CO2 is the fundamental step for bioprocessing designs based on SCF technology. Dynamic and static techniques are commonly adopted for solubility measurements in SC−CO2 [5]. The dynamic technique is a quick and flow-through design. The Chrastil equation (Eq. (1)) describes the linear relationship between a solute’s solubility and

SC−CO2 density [19], where a steady-state equilibrium of the solute and SC−CO2 is established for a continuous process. lnC=kln+c 1 /T +c 0

(1)

where C is the solute solubility (g/L),  the solvent density (g/L), T the operating temperature (K), and k, c1 and c0 the equation constants. The static technique is time consuming and relatively complex, but its controlled recirculation assures a more accurate phase equilibrium solubility of the solutes in SC−CO2 . Modeling solubility data using the “equations of state” provides more theoretical information on phase equilibrium solubility and P-V-T relationships among the solutes and SC−CO2 . Peng-Robinson equation of state (Eq. (2)) has been reported for modeling the binary phase equilibrium of biobased monomers, such as L-lactide or ␻-pentadecalactone, and SC−CO2 [20,21]. The results suggest that more SC−CO2 diffuses into the solute-rich phase with elevation of operating pressure. Adding less than 5% cosolvents, such as ethanol, can improve polarity of SC−CO2 and enhance the solubilities of polymeric monomers. As a result, a homogenous phase of the monomers and SC−CO2 can be reached at a relatively low pressure. P = RT/(–bm )–am /[(+bm ) + bm (–bm )]

(2)

where P is the pressure, R the gas constant, T the temperature,  the molar volume, and am and bm the equation parameters. 1.2. Biodegradable polyesters Applications of biodegradable polyesters range from microcapsules and fine particles for drug delivery to medical implants and porous scaffolds for tissue engineering [22–24]. A biodegradable polymer must meet very specific criteria: biocompatibility, prolonged circulation time, sufficient mechanical strength, and biomimetic degradation kinetics matching physiological processes, such as wound healing and tissue regeneration [25]. Chemical structures and typical synthesis processes of polyesters are presented in Fig. 1. Polyglycerol sebacate (PGS) is a resilient bioresorbable elastomer for tissue engineering and drug delivery [26,27]. Hydrogel, due to its intense hydrophilic structure, can hold a significant amount of hydrophilic bioactives with

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Table 1 Typical physical properties associated with different fluid states [4]. State of Fluid Gas P = 1 atm (0.1 MPa) T = 15–30 ◦ C Liquid P =1 atm (0.1 MPa) T = 15–30 ◦ C Supercritical P = Pc a , T = T c a P = 4Pc , T = Tc a

Density (g/cm3 )

Diffusivity (cm2 /sec)

Viscosity (g/cm·sec)

(0.6–2) × 10−3

0.1–0.4

(1–3) × 10−4

0.6–1.6

(0.2–2) × 10−5

(0.2–3) × 10−2

0.2–0.5 0.4–0.9

0.7 × 10−3 0.2 × 10−3

(1–3) × 10−4 (3–9) × 10−4

Pc : critical pressure; Tc : critical temperature.

Fig. 1. Chemical structures and typical synthesis processes of aliphatic polyesters.

Table 2 Examples of biodegradable polymers and synthesis techniques. Name

Abbreviation

Technique

References

poly(glycerol sebacate) poly(␤-thioether ester) poly(butylene succinate) poly(tartronic-co-glycolic acid) poly(ethylene dodecanedioate-2,5-furandicarboxylate) poly(1,5-pentylene dicarboxylate)s, with diacid carbon chains from 2 to 10

PGS PTE PBS poly(TA-co-GA) PEDF PPeA, PPeS, PPeG, PPeAz, PPeSe, PPeDo coPBFS PLA PDO PBL PVL PLDO PCL

polycondensation polycondensation polycondensation polycondensation Transesterification polycondensation polycondensation

[26,50,137] [33] [138,139] [140] [141] [142]

ring opening polymerization ring opening polymerization ring-opening polymerization ring opening polymerization ring opening polymerization ring opening polymerization ring opening polymerization

[75] [42] [143] [144] [145] [94] [45,78]

poly(butylene furandicarboxylate-co-succinate)s poly(lactide) poly(dioxanone) poly(butyrolactone) poly(valerolactone) poly(L-lactide-co-p-dioxanone) Polycaprolactone

consistent controlled release [14,28]. More examples of commonly used polyesters and synthesis techniques are listed in Table 2. Polyesters can be synthesized using polycondensation, ring opening polymerization (ROP), or an integrated process. Mechanisms of these reactions are shown in Fig. 2. Polycondensation is usually carried out in apolar solvents or in the bulk. Most naturally occurring diacids have a high melting temperature (Tm )>100 ◦ C and very limiting solubility in apolar and aprotic media, such as toluene and methanol, which may be a restricting factor for the reaction rate. Nevertheless, polycondensation is relatively simple with repeating esterification throughout the entire process. ROP is a comparative rapid reaction with elongating polymer chain by means of adding the monomers at one end or both ends. Specific reactions, such as initiation, propagation, and termination, at different stages are required for ROP.

1.3. Lipases The lipases, a class of serine hydrolases, are stable in most organic solvents at moderate temperatures and can be used to catalyze esterification reactions under anhydrous status [29,30]. They remain active in a wide pH range. Undesirable side reactions can be avoided or eliminated [31]. The lipases are particularly applicable for polycondensation, transesterification, ROP, and modification of branched polymeric groups [16,17,32–34]. Immobilization of the lipases on water-insoluble supports, such as covalent bonding, entrapment in gels or hollow fibers, and adsorption on polymeric surfaces [35–38], has been reported for improved enzyme stability and reusability. Synthesized polymers can be directly separated from the immobilized lipases by filtration [18,37,39]. Several commonly employed lipases are listed in Table 3, with their specific uses in polymer syntheses.

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Fig. 2. Polycondensation and ring opening polymerization for polyester synthesis.

Table 3 Lipases employed in enzymatic polymerization. Enzymes

Reaction technique

Solvent

References

Candida antarctica Lipase B Porcine pancreatic lipase Pseudomonas cepacia lipase Burkholderia cepacia lipase Aspergillus niger lipase Mucor miehei lipase Pseudomonas fluorescens lipase Rhizomucor miehei lipase Burkholderia cepacia lipase Candida rugosa lipase Thermomyces lanuginosus lipase

polycondensation/ROP/esterification free radical polymerization/ Knoevenagel condensation ROP polycondensation Knoevenagel condensation esterification bulk ROP esterification polycondensation polycondensation polycondensation/emulsion polymerization

SC-CO2 /bulk dioxane bulk SC-CO2 DMSO propanol bulk bulk bulk toluene bulk/cyclohexane

[34,62] [63,146] [147] [17] [63] [148] [147] [37] [149] [149,150] [35,151]

Conventional techniques for polymerization have several drawbacks, such as high reaction temperature, prolonged reaction time, lack selectivity, and residue of toxic metal-contained catalysts. Polymerization using lipases can provide an alternative to solve the aforementioned issues [40]. Under anhydrous conditions, biodegradable polyesters can be synthesized via ring-opening polymerization (ROP) [16,41,42] and polycondensation [32,40]. The regioselectivity of certain lipases can generate linear long-chained prepolymers with preservation of specific functional groups for subsequent reactions such as crosslinking, dendrimerization, and branching [43]. As outlined in Fig. 3, the latest development of SCF technology in polymerization is summarized in this review. Lipase-catalyzed polymerization has drawn increasing attention in the last decade. Trends in related biomedical applications employing SC−CO2 polymerization will be addressed with the most successful examples.

ity in SC−CO2 . Remarkable solubility of SC−CO2 in the polymers induces more SC−CO2 diffusion into homogenous or heterogeneous reaction matrix. The polymeric matrix turns into a swollen and less viscous status, leading to a drastic decrease in the glass transition temperature (Tg ) of the matrix during polymerization. Improved plasticization, due to lower Tg by SC−CO2 diffusion, may facilitate mixing of monomers or initiator in the polymer-rich phase, especially for polycondensation [46,47]. Plasticization may also allow polymerization at a mild temperature, so as to prevent heat sensitive compounds from thermal degradation. No solvent residue in the final products makes the use of SC−CO2 particularly valuable in fabrication of biodegradable polymers for biomedical applications [1,48]. The newly developed techniques of polymerization in SC−CO2 are categorized and presented as follows.

2. Supercritical fluid technology in polymerization

Polycondensation of glycerol and diacids have gained increasing attention for biodegradable material synthesis [18,27,49,50]. Glycerol possesses three hydroxyl groups: two primary and one secondary. It has been approved by US Food and Drug Administration for medical applications. Various chemical reactions are involved with glycerol, such as hydrogenolysis, esterification, dehydration, and polymerization, for applications in biomedical engineering, agrochemical, and pharmaceutical industries [51].

SC−CO2 is a good plasticizing agent for synthesis of polymeric materials, including homopolymers, block copolymers, and polymer blends [34,44,45]. Mechanism of supercritical fluid polymerization is presented in Fig. 4. After SC−CO2 pressurization, coexistence of the SC−CO2 -rich and polymer-rich phases will reach phase equilibrium. Most polymers exhibit extremely low solubil-

2.1. Polycondensation

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Fig. 3. Supercritical fluid technology in polymerization and related biomedical applications.

Fig. 4. Mechanism of supercritical fluid polymerization.

A few challenges existing in conventional polycondensation, including high reaction temperature, long reaction time, and undesirable side reactions, can be overcome with polycondensation in SC−CO2 , due to its distinctive diffusing capability into the reacting polymeric matrix. When polymer chain elongates, viscosity of the melt can increase significantly during polycondensation, thus making stirring and processing more challenging. Swelling and plasticization of a polymer melt with SC−CO2 diffusion significantly reduce the melt viscosity and improve the mobility of condensates and polymer chain ends for higher yield of synthesized polymers and shortened reaction time. Polycondensation of poly(naphthoylenebenzimidazole) (PNBI) was performed in SC−CO2 at 15 MPa, 90 ◦ C, and reaction time of 8 h, with a mixed catalysts of benzoic acid and benzimidazole (molar ratio of 1 to 1) [52]. The yield of 95% was reached for PNBI synthesis with average size of 53 ± 14 nm. PNBI exhibits yellow-orange photoluminescence and can be adopted in light-emitting devices [52]. An integrated process using SCF polycondensation and foaming

for synthesis of polyethylene terephthalate (PET) was conducted in SC−CO2 at 280 ◦ C and 8 to 14 MPa with reaction time varying from 20 to 50 min [53]. Polymeric network of PET reached the highest degree of polymerization at the pressure beyond 10 MPa. After depressurization, the PET foams displayed the pore diameter ranging from 32 to 62 ␮m and pore density of 1 × 107 to 4 × 107 pores/cm3 . 2.2. Ring opening polymerization Ring opening polymerization (ROP) is a type of chain growth polymerization. The terminal ends of a polymer chain act as a propagating center, where more cyclic monomers can react by opening their ring structure, for elongation of polymer chains. The propagating center can be a radical, anionic, or cationic group. ROP can be conducted through two major mechanisms if organometallics are involved in the chain growth reaction. In the first mechanism, the organometallic acts as a catalyst and activates the monomers

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by complexation with their carbonyl group. ROP is then initiated by nucleophiles, such as water or ethanol, in the reacting medium [54,55]. In the second mechanism, the organometallic plays a role of initiator and polymerization advances through a coordinationinsertion reaction. Metal alkoxides are the typical initiators for ROP, which first coordinates the carbonyl groups of the monomers, followed by cleavage of the acyl-oxygen bond of the monomers with simultaneous insertion of a propagating polymer into the cleavage site for further polymer elongation on the terminal ends [55]. An integrated process of ROP and polycondensation of D,Llactide and D-sorbitol was developed for synthesis of branched sorbitol polylactic acid (S-PLA) in SC−CO2 at 95 ◦ C, 24 MPa, and reaction time of 3 h, with tin 2-ethylhexanoate as the initiator [56]. Polymerization of D,L-lactide was first performed via ROP in SC−CO2 for elongation of linear polymer chains. At molar ratios of 40 : 1 and 80 : 1 for poly(D,L-lactide) to D-sorbitol, the globular structure of branched S-PLA was synthesized in SC−CO2 via polycondensation, with Mn ranging from 6800 to 9800 Da and PDI of 1.1. The metal catalyst was directly removed by purging S-PLA with SC−CO2 at 45 ◦ C and 24 MPa for 45 min. S-PLA is recognized as a nontoxic biodegradable surfactant, significantly reducing water surface tension from ∼70 to ∼40 mN/m [56]. The need of multi-step purification for toxic solvent removal and high energy consumption for vacuum devolatilization were eliminated for the newly developed process. 2.3. Enzymatic polymerization Polymerization by lipase-mediated catalysis is among the most attractive biochemical and bioengineering processes [34]. Syntheses of biodegradable polymers with lipase catalysis can assure linear polymeric structure and reach higher molecular weight in shortened reaction time. Specific functional groups on the polymeric chain can be reserved for subsequent reactions such as crosslinking, dendrimerization, and branching [43]. The lipase was first applied for transesterification of tributyrin and primary/secondary alcohols three decades ago [29,30]. In nature, the lipase functions as a hydrolase to decompose lipids into fatty acids and glycerol in physiological conditions. Under anhydrous status, the lipase catalyzes in the reverse direction to esterify acids with polyols for biofuels and biodegradable polymers [17,34,45,57–59]. Syntheses of biodegradable polyesters with lipase catalysis can be conducted via ring opening polymerization (ROP) [16,34,41,58,60], polycondensation [59,61,62], or an integrated process [32,53,63], as presented in Fig. 2. In polycondensation, the lipase catalysis offers high selectivity on primary hydroxyl groups of polyols. The protection-deprotection strategy can be eliminated for improved quality of synthesized polymers. Lipase-catalyzed synthesis has been focused on homo/copolymerization of a number of biobased monomers [32,33,58,64]. This enzymatic polymerization exhibits very high chemo-, regio-, and enantio-selectivities and involves a number of advantageous characteristics, such as milder reaction temperature and lower activation energy [65]. In polycondensation of divinyl sebacate and 1,2,6-hexanetriol at 30 ◦ C, the regioselectivity of Candida antarctica lipase B (CALB) gave the control of polymer chain linearity consisting of 1,6-disubstituted units exclusively [43]. It has been reported that lipases show comparable enzymatic activities in organic solvents and SC−CO2 [29,30,66]. SC−CO2 has been attempted to develop milder reaction processes for biopolymer syntheses as well as a green substitute for organic solvents. 2.3.1. Lipases from different sources Due to subtle structural differentiation on the active site, different lipases have been evaluated for their catalytic activities. A list of commonly used lipases was exhibited in Table 3. The lipase-

catalyzed esterification of propionic acid and isoamyl alcohol was carried out in SC−CO2 at 50 ◦ C and 10 MPa, with Candida antarctica lipase B (CALB), Candida rugosa lipase, Thermomyces lanuginosus lipase, and porcine pancreatic lipase. It was found that isoamyl propionate catalyzed by CALB reached the highest degree of esterification [67]. 2.3.2. Mechanism Lipases perform catalysis via a motif comprising serine, histidine and aspartate/glutamate in the order [68]. The role of lipases as biocatalysts is based on the “key and lock” mechanism [69]. An overview of lipase-catalyzed polymerization in SC−CO2 is presented in Fig. 5. It has been reported that a fatty acid forms an acyl-enzyme intermediate complex with the lipase, releasing a water molecule and then binding an alcohol onto this enzyme-acyl complex. The intermediate is then transformed into a enzymeester complex followed by releasing the ester and free enzyme [68]. Enzymatic activity can be modeled using Michaelis-Menten kinetics. Under anhydrous conditions, the lipase favorably reacted with the primary alcohols [30]. During CALB-catalyzed polycondensation of oleic diacid and glycerol, unfavorable hyperbranching reactions were avoided due to steric hindrance at the active site of lipases [62]. Syntheses of semi-aromatic and aromatic polyesters by lipasecatalyzed polymerization exhibit limited conversion rate [70]. This can be attributed to the lack of reactivity of aromatic monomers under mild reaction conditions and low solubility of the relevant polymers in SC−CO2 . Early precipitation of these two aromatic polymers may occur during synthesis reactions, leading to inefficient contact with the active site of lipases for further chain elongation and higher degree of polymerization [71]. 2.3.3. Effects of operating parameters Most lipases require a trace amount of water (<5%) to keep the catalytic site active [72]. Above this limit, excessive CO2 dissolved in water would lower pH < 3. Esterification capability of the lipase would be limited due to potential acidic denaturation in SC−CO2 , resulting in shortened polymer chains with lower molecular weight [73]. In a CALB-catalyzed polymerization of ␻pentadecalactone in SC−CO2 at 20 MPa and 70 ◦ C [34], reducing water content of the lipase from 1.74 to 0.77 wt% increased Mw of poly(␻-pentadecalactone) from 52,400 to 66,600 Da. With sufficient reaction time, molecular weight and yield would be significantly increased in lipase-catalyzed polymerization [74,75]. Synthesis of poly(oleic diacid-co-glycerol) was conducted using enzymatic polycondensation. With CALB catalysis on the equimolar mixture of oleic diacid and glycerol, Mn of the polyester increased from 2300 g/mol at 2 h to 9100 g/mol at 24 h. Low branching percentage varying from 13% to 16% was reported. PDI of the synthesized polyester was measured to be 1.9 at 2 h and maintained around 3.4 from 4 to 24 h [5]. The lipases are thermally stable up to 85–90 ◦ C. Raising reaction temperature during lipase-catalyzed polymerization can specifically increase molecular weight of synthesized polymers [33,75]. Polymerization of divinyl sebacate and 1,2,6-hexanetriol catalyzed by CALB at 30 ◦ C gave PGS a low Mw of 1900 g/mol. With reaction temperature raised from 30 to 45 ◦ C, Mw of the synthesized polyester increased up to 13,000 g/mol. [43]. Catalytic activity and reusability can be improved with immobilization of the lipases on or within solid supports, such as silica gel, chitosan, and acrylic resins, through covalent bonding, encapsulation, and adsorption [35–38]. Developing effective immobilization techniques to stabilize enzyme structure and activity is a determining factor for success of enzymatic polymerization [38,76]. Candida rugosa lipase (CRL) was covalently deposited onto polymer-grafted silica nanoparticles (p-SNPs) [77]. It was reported that the catalytic

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Fig. 5. Lipase catalysis for biodegradable polymer synthesis: (A) Conformation of Thermomyces lanuginosus lipase with catalytic site [152]. (B) Lipase-catalyzed polymerization of ␧-caprolactone in SC−CO2 at 65 ◦ C and 12 MPa using immobilized CALB [78]. (C) Mechanism of lipase-catalyzed esterification [153]. Sources: [152], Copyright 2017. Reproduced with permission from Frontiers Media Ltd.; [78], Copyright 2013. Reproduced with permission from Elsevier Ltd.; [153], Copyright 2012. Reproduced with permission from the Brazilian Archives of Biology and Technology (Technology Institute of Paraná).

activity of p-SNPs-CRL was two to four times higher than free CRL in the temperature range of 25–60 ◦ C. Immobilization improved the enzyme stability. SNPs-CRL held more than 50% of the initial activity after nine consecutive uses for enzymatic polymerization. During the storage test of 70 days, SNPs-CRL retained 90% of its original catalytic activity whereas the corresponding value for free CRL was only 52% [77].

2.3.4. Examples for enzymatic polymerization in SC−CO2 Lipase-catalyzed ROP synthesis of poly(␧-caprolactone) in SC−CO2 was conducted at 12 MPa, 65 ◦ C, and SC−CO2 to monomer mass ratio of 1 to 2 [78]. The poly(␧-caprolactone) reached Mw of 22,200 Da with PDI ranging from 1.2 to 1.7. Reaction yield rising up to 90% was reported when the concentration of immobilized CALB was increased from 1 to 15 wt% [78]. Porous scaffold of polycapro-

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Fig. 6. Drug loading in biodegradable polymeric matrix prepared in SC−CO2 for controlled release: (A) 5-fluorouracil loaded in porous PCL scaffold [79]; (B) Insulin encapsualted in PLLA microspheres [81]. Sources: [79], [81], Copyright 2019, 2015, respectively. Reproduced with permission from Elsevier Ltd.

Fig. 7. SEM images of PVDF from homogeneous polymerization in SC−CO2 at 140 ◦ C and 15 MPa with 0.307 mol/L DTBP as initiator. [84], Copyright 2007. Reproduced with permission from John Wiley & Sons Inc.

lactone can be generated using SC−CO2 foaming at 20 MPa, 50 ◦ C with reaction time of 17 h [79]. The density of polymeric scaffold varied from 0.2 to 0.5 g/cm3 with average pore size of 300 ␮m. Loading efficiency of 5-fluorouracil, an anticancer drug, in the polymeric scaffold reached 30 wt% for the study of controlled release. Fig. 6(A) shows morphology of the 5-fluorouracil-loaded PCL scaffold. Poly(␻-pentadecalactone) was successfully synthesized via CALB-catalyzed ROP in SC−CO2 at 20 MPa and 70 ◦ C with reaction time of 2 h [34]. The highest Mw of 66,000 g/mol was reached with PDI of 3.8 and yield of 61%. The polymeric scaffold made with poly(␻-pentadecalactone) exhibits desirable mechanical properties and biocompatibility for bone and cartilage tissue regeneration [34]. Lipase-catalyzed ROP of L-lactide was conducted in SC−CO2 at 30 MPa and 60 ◦ C with reaction time of 72 h. The synthesized polyL-lactide (PLLA) reached the Mw of 11,900 g/mol and PDI of 1.25 with semi-crystalline structure [80]. Porous microspheres of PLLA, with the mean diameter of 15.6 ␮m, were generated using antisolvent process in SC−CO2 . Loading efficiency of 6.9% was reached for controlled release of insulin [81]. The microcellular PLLA structure with microencapsulated insulin is shown in Fig. 6(B). Polycondensation of azelaic acid (nonanedioic acid) and 1,6hexanediol was catalyzed by immobilized CALB in SC−CO2 at 27.5 MPa and 35 ◦ C. Sorbic acid, 12-hydroxy-stearic acid, trimethylolpropane oxetane, and 2-hydroxyethyl methacrylate were used as end cappers to produce small prepolymers with molecular weight ranging from 1160 to 1230 g/mol. The yield of prepolymers with different end cappers varied from 78 to 86% and conversion rate was higher than 96% [59]. The synthesized macromolecules can be further reacted to prepare biodegradable films and functional coatings on biomedical devices.

2.4. Homogeneous polymerization A homogenous phase consisted of reacting monomers, initiators, and SC−CO2 is maintained during polymerization. The polymers remain dissolved in SC−CO2 for propagation until depressurization. Homogeneous SC−CO2 polymerization has been reported to synthesize amorphous fluoropolymers through free radical reactions or cationic chain growth. The resultant polymers with relatively low molecular weight are always generated using this SCF technique [82]. Homogeneous polymerization of vinylidene fluoride (VF2) with hexafluoropropylene (HFP) was conducted in SC−CO2 at 31 MPa and 35 ◦ C, using perfluorobutyryl peroxide (PBP) as initiator. The synthesized copolymer, poly(VF2-co-HFP), exhibited amorphous and elastomeric properties with Mn of 16.1 kDa and PDI of 1.63 [83]. Synthesis of polyvinylidene fluoride (PVDF) was carried out with homogeneous polymerization in SC−CO2 at 150 MPa and 140 ◦ C [84]. Di-tert-butyl Peroxide (DTBP) was used as the reaction initiator. The Mn of PVDF ranged from 2700 to 7700 g/mol with PDI of 3.1 to 5.7. Scanning electron microscopy (SEM) indicated that PVDF exhibited an amorphous polymeric structure in Fig. 7 [84]. 2.5. Precipitation polymerization A homogenous phase exists due to high miscibility of monomers, initiators, and SC−CO2 . During rapid propagation, the polymers with fast-growing molecular weight precipitate out of the fluid phase and are directly harvested as dry powders after depressurization. Precipitation polymerization in SC−CO2 can be initiated with cationic ions or free radicals. CO2 is relatively inert to this synthesis process. Polymerization occurs without incorporation of

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CO2 in the polymer backbone. Mild operating temperature can also reduce side reactions, such as chain transfer or early termination. Poly(vinyl acetate) (PVAc) was synthesized in SC−CO2 at 30 MPa and 45 ◦ C, with an alkyl-cobalt (III) initiator [85]. The PVAc began to precipitate out of the reacting matrix when Mn exceeded 10,000 g/mol. The highest Mn of 28,500 g/mol with PDI of 1.97 was reached at reaction time of 61 h. This newly developed process opens new perspectives for macromolecular engineering in SC−CO2 without the utilization of fluorinated comonomers or organic solvents [85]. Synthesis of poly(N-isopropylacrylamide) (PNIPAAm), a temperature responsive polymer, was conducted using precipitation polymerization in SC−CO2 at 27.6 MPa and 55 ◦ C, with AIBN as the initiator [86]. For the reaction time of 10 h, Mw of PNIPAAm increased from 31,800 to 87,100 g/mol with PDI of 1.1 to 1.5, when the operating temperature was raised from 35 to 60 ◦ C. Free radical polymerization for synthesis of poly(2-methylene1,3-dioxepane) (PMDOP) was conducted using precipitation polymerization in SC−CO2 [87,88]. The operating condition was set at 30 MPa and 70 ◦ C. 220-Azobisisobutyronitrile (AIBN) was employed as the initiator. The synthesized PMDOP in SC−CO2 exhibited PDI of 1.5 and low branching degree, compared to PMDOP generated in bulk polymerization at 55 ◦ C with PDI of 9.7 and obvious gel formation [88]. Copolymerization of MDOP and Nvinyl-2-pyrrolidone (NVP) in SC−CO2 was also demonstrated for controlled polymer morphology. With the feeding molar ratio of MDOP increasing from 0 to 79.6%, Tg was drastically decreased from 146 to −53 ◦ C. Improved amorphous property was achieved for fine particle formation and microencapsulation for drug delivery with controlled release [88]. SC−CO2 is a good solvent to many CO2 -philic monomers for precipitation polymerization. However, insolubility of the propagating polymer may hamper reaction efficiency. 2.6. Dispersion polymerization To overcome the drawback of precipitation polymerization, dispersion polymerization is developed, where a reacting mixture is stabilized by adding a small amount of an appropriate stabilizer or surfactant. This stable suspension is typically termed as a polymer dispersion, colloidal dispersion, or latex. Stabilization mechanism in dispersion polymerization is referred to the steric effect. A layer of stabilizer, adhered at the interface between the growing polymer and solvent, provides a long-range steric repulsion for continuous growth of polymer chains. The synthesized polymer using dispersion polymerization appears as spherical particles with the size ranging from 0.1 to 10 ␮m [89]. The stabilizer generally consists of monomer/polymer-philic anchors and CO2 -soluble groups, such as fluorine or siloxane groups. The size and balance of the anchors and CO2 -soluble groups (anchor to soluble balance) are the determining factors in success of this technique [90,91]. Dispersion polymerization of polymethyl methacrylate (PMMA) in SC−CO2 was conducted at 20 to 40 MPa and 70 ◦ C [92]. Three comblike fluorinated polymers with different lengths of CO2 -philic fluorocarbon chains, -C2 F5 , -C6 F13 , and -C8 F17 , were evaluated respectively for their stabilization capability. The average size of PMMA decreased from 4 to 1 ␮m with increasing CO2 -philic chain. Spherical PMMA particles were observed with using all of three stabilizers in polymerization [92]. Synthesis of poly(2-hydroxyethyl methacrylate) (PHEMA) was achieved with dispersion polymerization in SC−CO2 at 38.5 MPa, 65 ◦ C for 15 h [93]. AIBN was used to initiate the polymerization with a photocleavable stabilizer, PEOhv-PFDA, for stability of the polymer dispersion. The synthesized PHEMA exhibited Mn of 23,000 g/mol and particle size of 348 nm with PDI of 1.17. After UV irradiation, PEO-hv-PFDA was photocleaved and removed by SC−CO2 extraction. The purified PHEMA

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formed stable nanogels with water for longer than 24 h, which can be employed as a drug delivery carrier [93]. 2.7. Emulsion polymerization Emulsion polymerization is a typical radical-based reaction that begins with an emulsion consisting of monomers and surfactant in SC−CO2 . The initiator is then solubilized in the SC−CO2 phase, where initiating radicals are generated. A fluorinated surfactant, such as perfluoropolyether, is commonly employed for emulsion stabilization. Lipophilic monomers would form the micellar emulsion in SC−CO2 for synthesis of hydrophobic polymers. The polymerization occurs inside the micelles, which are suspended in the continuous SC−CO2 phase. Biodegradable poly(L-lactide-co-p-dioxanone) (PLDO) was synthesized in SC−CO2 with stannous octoate as the ring opening catalyst. A fluorinated triblock stabilizer, polycaprolactone-bperfluoropolyether-b-polycaprolactone (PCL-PFPE-PCL) was used to stabilize the emulsion [94]. Emulsion polymerization was conducted in SC−CO2 at 24.1 MPa and 80 ◦ C for 24 h. The synthesized polymer had Mn ranging from 15,000 to 26,000 g/mol with PDI of 1.3 to 2.1. Fine particle size varying from 10 to 100 ␮m was observed for PLDO composed of L-lactide and p-dioxanone in weight ratio of 9 to 1. Inverse emulsion polymerization is developed to overcome low miscibility between coexisting hydrophilic monomer solution and SC−CO2 . This technology leads to the formation of a water-in-oil (W/O) emulsion where the polymers with very high molecular weight are trapped in the aqueous core. Inverse emulsion polymerization has the advantage of attaining macromolecular polymers and reaching high reaction rates simultaneously. Polymerization takes place almost exclusively in the aqueous droplets. Hydrophilic monomers do not effectively compete with growing polymers for capturing radicals in aqueous droplets, due to much smaller surface area of the monomers. A superabsorbent polymer, poly(acrylic acid) (PAA) was synthesized in SC−CO2 using inverse emulsion polymerization [95]. Acrylic acid (AA) was dissolved in sodium hydroxide (NaOH) solution, followed by neutralization to form sodium acrylate. N,N’methylene-bisacrylamide at 0.1 to 0.5 wt% as the crosslinker and sodium persulfate as the initiator were added into the aqueous solution. The AA solution was then loaded into a high-pressure reactor filled with SC−CO2 at 11 MPa and 75 ◦ C for 1 h, with 40 ppm of siloxane copolymers as the emulsion stabilizer. The polymeric particles were generated in the size ranging from 200 to 800 ␮m with particle yield rate of 64%. Based on the test of absorption under load (AUL), the crosslinked and partially neutralized PAA exhibited similar water absorbency when compared to the commercial products. 2.8. Reversible addition-fragmentation chain transfer (RAFT) RAFT polymerization in SC−CO2 has been successfully developed for polymer synthesis with controlled molecular weight and low polydispersity (Ð<2) by means of equal growth of propagating polymeric chains [96]. With a specially designed RAFT agent composed of thiocarbonylthio compounds, polymer morphology can be architected as comb-like, star, and brush structures for specific applications. Free radicals are sufficiently imparted by the RAFT agent while the initiators continuously decompose during polymerization. A microparticulate block copolymer, composed of methyl methacrylate (MMA) and 4-vinylpyridine (4 V P), was synthesized via RAFT polymerization in SC−CO2 at 27 MPa and 65 ◦ C for 20 h [97], with AIBN as the initiator and 2(Dodecylthiocarbonothioylthio)-2-methylpropionic acid (DDMAT)

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Fig. 8. SEM images of RAFT polymerization in SC−CO2 : (A) Poly(styrene-co-divinylbenzene) [98]; (B) Poly(MMA-co-EGDMA) [99]. Sources: [98], Copyright 2012. Reproduced with permission from CSIRO Publishing. [99], Copyright 2013. Reproduced with permission from the Taylor & Francis Group.

Fig. 9. Encapsulation of coumarin 6 (C6) in polymeric capsules [102]: (A) TEM image of the micelles constituted with the copolymer, MPEG12 -PHAz6 -MPEG12 ; (B) Suspension of the polymeric capsules encapsulating coumarin 6 in aqueous medium. Source: [102], Copyright 2016. Reproduced with permission from the Royal Society of Chemistry.

as the RAFT agent. The highest Mn of 59,400 kDa was reached with the molar ratio of 0.64 to 0.36 for MMA and 4 V P. The porous structure of PMMA-b-P4 V P was generated by swelling in ethanol and deswelling in hexane. The molar ratio of 4 V P raised from 0.09 to 0.36 increased the pore size from 112.7 to 168.8 nm. Pore connectivity was first observed under SEM with the molar ratio of 4 V P>0.2 [97]. Copolymerization of styrene and divinylbenzene in SC−CO2 was conducted at 30 MPa and 80 ◦ C, with S-thiobenzoyl thioglycolic acid (TBTGA) as RAFT agent and dibenzoyl peroxide (BPO) as initiator [98]. The highest Mn of 17,344 Da and PDI of 1.26 were reached for the synthesized copolymer with desirable swelling capacity and porous structure, as shown in Fig. 8(A) [98]. RAFT polymerization of methyl methacrylate (MMA) and ethylene glycol dimethacrylate (EGDMA) was performed in SC−CO2 at 17.2 MPa, 65 ◦ C, and reaction time of 16 h. AIBN was used as initiator with TBTGA as RAFT agent [99]. Mn ranging from 118,000 to 130,000 g/mol and PDI of 1.05 to 1.3 were achieved for poly(MMA-co-EGDMA) with spherical morphology, as shown in Fig. 8(B). 3. SCF polymerization in related biomedical applications Biodegradability and biocompatibility are the main prerequisites to design a polymeric biomaterial for current medical research. Fig. 3 illustrates the related biomedical applications with the SC−CO2 processes in polymerization. Use of organic solvents would be drastically reduced or eliminated. In addition to shortened processing time, polymeric materials fabricated in SC−CO2 exhibit tunable microcellular structure and controlled mechanical properties. Current progress includes microcapsule generation,

microcellular scaffold fabrication, and the SC−CO2 -assissted processes, such as impregnation, aerogel formation, and sterilization. 3.1. Microcapsule generation for drug delivery 3.1.1. Lipase-catalyzed polycondensation Formation of micelles and polymeric vesicles composed of amphiphilic copolymers can be applied for drug encapsulation and delivery systems [100,101]. Synthesis of an amphiphilic block copolymer, consisting of azelaic acid and 1,6-hexanediol (PHAz) with the end capper, methoxy polyethylene glycol (MPEG), was conducted using Candida antarctica lipase B (CALB)-catalyzed polycondensation in SC−CO2 at 27.5 MPa, 35 ◦ C for 24 h [102]. The synthesized polymer, MPEG12 -PHAz6 -MPEG12 , was produced with Mn of 3200 g/mol, PDI of 2.24, and yield rate up to 87%. This semicrystalline polymer exhibited an average vesicular size of 231 nm in water dispersion. Encapsulation efficiency of coumarin 6 (C6), a model lipophilic compound, in MPEG12 -PHAz6 -MPEG12 was reported to be three to five times higher than those in commercial amphiphilic copolymers, such as Tween 20 and Pluronic. Morphology and emulsion appearance of polymeric capsules are presented in Fig. 9. 3.1.2. Dispersion polymerization Dispersion polymerization of 2-hydroxyethyl methacrylate (HEMA) was conducted in SC−CO2 at 30 MPa, 35 ◦ C, and reaction time of 24 h for microencapsulation of proline-replaced temporin L analogue (Pro3 -TL), an antimicrobial peptide [103]. Ethylene glycol dimethacrylate (EGDMA) was employed as a crosslinker with 2,20 -Azobis(4-methoxy-2,4-dimethylvaleronitrile) as a stabilizer.

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Fig. 10. SEM images of the poly(HEMA) particles encapsulating with (A) initial sulindac loading of 0.1 wt% and (B) initial sulindac loading of 1 wt%. [104], Copyright 2018. Reproduced with permission from Elsevier Ltd.

The SEM image indicated that the HEMA capsules encapsulating Pro3 -TL exhibit spherical shape with the average size of 432 nm. Good swelling capability in aqueous solution was observed as formation of hydrogel. The bactericidal effect against Staphylococcus aureus lasted for 24 h with controlled release of the antimicrobial peptide from swollen hydrogels [103]. Microencapsulation of sulindac, an anti-proliferative and antiinflammatory drug, in poly(HEMA) crosslinked microcapsules was conducted via dispersion polymerization in SC−CO2 at 30 MPa, 35 ◦ C, and reaction time of at least 18 h, with the crosslinker, EGDMA, and the photocleavable stabilizer, PEO-h-PFDA [104]. As shown in Fig. 10, these crosslinked microcapsules were obtained with well-defined spherical morphology and the size varied from 250 to 350 nm. Redispersed in water, swollen microgels were formed with the size ranging from 2.1 to 3.6 ␮m. Encapsulation efficiency of sulindac in poly(HEMA) microgels reached 86% with a first-order release rate up to 10 days [104].

3.1.3. Precipitation polymerization Precipitation polymerization of N-isopropyl acrylamide (NIPA) and acrylic acid (AA) was conducted in SC−CO2 at 12 MPa and 35 ◦ C for 5 h, with AIBN as the initiator [105]. The synthesized copolymer with thermo and pH responsivities was grafted into the matrix of vinyl-functionalized mesocellular silica foam (MCF). 5-fluorouracil, an anticancer drug, was then impregnated on the copolymer coated surface of MCF using SC−CO2 impregnation for targeted delivery study. As shown in Fig. 11, the TEM image indicated the spherical shape of the polymer−COated MCF with the size ranging from 100 to 150 nm. The loading efficiency of 5-fluorouracil reached 11.5 wt% after SC−CO2 impregnation. Heat induced release of 5-fluorouracil was controlled with poly(NIPA-co-AA) grafted MCF.

3.2. Fabrication of microcellular scaffolds 3.2.1. SC−CO2 foaming A microcellular scaffold should display high porosity, uniform pore distribution, and enhanced pore interconnectivity in the polymeric matrix for regenerative tissue supports and lightweight structural materials [106]. SC−CO2 is a particularly ideal foaming alternative for fabrication of microcellular scaffolds, compared to conventional processes where a large volume of porogenic organic solvents is required under high temperature operation. Solvent residues in the resultant scaffolds can be avoided due to immediate evaporation of CO2 at ambient pressure [106]. The microcellular scaffolds fabricated using SC−CO2 foaming also achieve high cell survival rate and effective proliferation in osteogenesis [107].

Glass transition temperature (Tg ) of the polymer would be significantly decreased by diffusion and plasticization of SC−CO2 in the polymer-rich phase during scaffold formation, where the reacting matrix is expanded and viscosity is reduced. During depressurization, thermodynamic instability leads to supersaturation of dissolved CO2 in the matrix, followed by cellular network formation where fluid nuclei are formed [108]. These nuclei would further grow upon CO2 evaporation out of the matrix. During CO2 depressurization, collapse of microcellular structure is prevented with fortified scaffold strength, resulting from rising viscosity and crystallization taking place simultaneously. As shown in Fig. 12, porous polymeric structure can be generated with subsequent reduction in the scaffold apparent density. The depressurization rate of SC−CO2 and matrix cooling rate play the key roles in controlling pore nucleation/growth and pore interconnectivity [109–111]. The challenge has yet to be overcome when this technique is applied for synthesis of the polymer with high crystallinity or high Tg . Porous polycaprolactone (PCL) scaffolds encapsulating triflusal, an anti-inflammatory drug, was fabricated using SC−CO2 foaming at 20 MPa and 40 ◦ C for 1 h [112]. Encapsulation efficiency of triflusal in the PCL scaffold reached 52.4%. With depressurization rate of 4 MPa/min, a polymeric structure was formed with average pore size of 87 ± 27 ␮m and porosity of 61%. Controlled release of triflusal from the PCL scaffold followed the first-order release kinetics with cell survival rate >80% [112]. Graf copolymerization of L-lactic acid (LA) onto starch with stannous 2-ethyl hexanoate (Sn(Oct)2 ) as a catalyst was conducted in SC−CO2 at 20 MPa and 100 ◦ C for 6 h [113]. The Sn(Oct)2 -catalyzed reaction of starch and LA was accelerated in SC−CO2 , where the viscosity of reacting matrix was reduced due to SC−CO2 diffusion into the expended melt. A maximum grafting degree of the copolymer was reached at 52 ± 2.3% with the pore size ranging from 1 to 5 ␮m during SC−CO2 foaming at a flow rate of 10 g/min. Thermogravimetric analysis indicated that this grafted copolymer exhibited better thermal stability than unprocessed starch. This copolymer can be used as a porous fiber and microcellular scaffold in tissue engineering [113]. Human platelets contain essential growth factors (GFs) for angiogenesis, wound healing, and osteogenesis [114]. The microcellular polymeric scaffold, fabricated using SC−CO2 foaming, would offer a protective depot with enhanced porosity and improved pore connectivity for controlled release of GFs to achieve functionalized tissue engineering. Integrating coacervation and SC−CO2 foaming, platelet lysate (PL) was first loaded in the chitosan/chondroitin nanoparticles and mixed with poly(D,L-lactic acid) (PDLLA) [107]. The mixture was processed with polymer plasticization and hybrid scaffold formation in SC−CO2 at 20 MPa and

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Fig. 11. Coating of poly(NIPA-co-AA) with 5-fluorouracil on mesocellular silica foam (MCF; the dark coresz) [105]: (A) The TEM image of MCF/P(NIPA-co-AA); (B) The cumulative release curve of 5-fluorouracil-loaded MCF/P(PINA-co-AA). Source: [105], Copyright 2017. Reproduced with permission from Springer Nature.

Fig. 12. Morphology of dexamethasone-loading PLGA scaffolds fabricated using SC−CO2 foaming [111]: (A) Porous PLGA scaffolds; (B) Dexamethasone loading in porous PLGA scaffolds. Source: [111], Copyright 2018. Reproduced with permission from John Wiley & Sons Inc.

Fig. 13. The PLLA scaffold prepared by supercritical phase inversion process [117]: (A) Physical appearance; (B) SEM image of the nanostructured scaffold. Source: [117], Copyright 2013. Reproduced with permission from Elsevier Ltd.

35 ◦ C for 30 min, followed by a depressurization rate of 0.5 MPa/min during SC−CO2 foaming. The bioactive scaffold exhibited a pore size ranging from 200 to 400 ␮m and porosity of 56 to 67%. Human adipose-derived stem cells (hASCs) were seeded onto the scaffold and displayed a faster osteogenic differentiation by stimuli from PL entrapped in the PDLLA scaffold. Concentrated from the supernatant during human buffy coat separation, the preparation rich in growth factors (PRGF) can synergistically stimulate cell proliferation and induce bone tissue regeneration. Composed of poly(␧-caprolactone) and gelatinized corn starch, the microcellular hybrid scaffold containing PRGF was generated using SC−CO2 foaming at 10 MPa and 37 ◦ C for 30 min, followed by depressurization at 1.5 MPa/min [115]. The PCL/starch scaffold exhibited porosity of 53% and average pore size of 0.45 ␮m. Encapsulation efficiency of PRGF reached 100% in the scaffold, with retained activity of 92.16 ± 9.44% after SC−CO2 foaming. Well con-

trolled release of PRGF from the PCL/starch scaffold was achieved and lasted for 120 h. High attachment and proliferation of mesenchymal stem cells (MSCs) were observed in 7 days after seeding in this hybrid scaffold containing PRGF. 3.2.2. Phase inversion Phase inversion is a process for polymer transformation from a liquid phase to solid phase [116]. The phase inversion method, also known as immersion precipitation technique, involves loading a polymer solution onto an inert support, followed by immersion of the support with cast polymer into a bath filled with a nonsolvent. The contact between the polymer solution and nonsolvent leads to phase separation for scaffold formation. Using SC−CO2 as a nonsolvent presents several advantages to phase inversion technique. By simply tuning process parameters, such as operating pressure and temperature, the polymeric structure can be tailored for specific

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Fig. 14. SEM images of porous scaffolds composed of 80% PCL and 20% HA and processed in SC−CO2 for impregnation of Usnea lethariiformis extract [118] at (A)17 MPa, 35 ◦ C and reaction time of 3 h and (B) 30 MPa, 35 ◦ C and reaction time of 3 h. Source: [118], Copyright 2016. Reproduced with permission from Elsevier Ltd.

demands. Structural collapse on the porous polymeric scaffold can be avoided during SC−CO2 drying, because no surface tension exists in absence of a liquid/vapor interface in SC−CO2 . A trace amount of solvent residues in the synthesized polymer can be completely removed with posttreatments of SC−CO2 flushing for purification, where sterilization is performed simultaneously during SC−CO2 depressurization [116]. The nanostructured scaffold was fabricated with poly(L-lactide) (PLLA) using phase inversion in SC−CO2 [117]. For the optimized condition, PLLA was dissolved in 1,4-dioxane and thoroughly blended with 10 wt% porogens, ammonium bicarbonate (AB) possessing particle size ranging from 300 to 600 ␮m and decomposition temperature of 36 ◦ C. The mixture was loaded in a high-pressure vessel filled with SC−CO2 at 15 MPa and 35 ◦ C for reaction time of 2 h. Polymer-rich phase was separated from the fluid-rich phase. Interconnected porous tunnels were observed inside the PLLA matrix. Scaffold purification using SC−CO2 flushing with a flow rate of 5 g/min at 15 MPa and 40 ◦ C was adopted to decompose the AB particles and to remove 1,4-dioxane. As shown in Fig. 13, the PLLA scaffold displayed a uniform nanofibrous structure with average pore size less than 10 ␮m, porosity of 92%, and good compressive strength of 225.4 kPa.

3.3. The SC−CO2 -assisted processes for polymer synthesis and applications 3.3.1. Impregnation Surface modification on the polymeric scaffold using SC−CO2 impregnation takes advantages of its high diffusivity, no surface tension, and simplified separation, to incorporate functional compounds or pharmaceuticals into the microcellular matrix. The targeted compound reaches saturated solubility in SC−CO2 with sufficient equilibrium time and carried out into the scaffold by the solute-laden stream. During rapid depressurization, the compound deposits on the matrix surface of porous or fibrous scaffolds. This bioactive support can be used as an implant for tissue regeneration or drug eluting stent with controlled release. An integrated SCF process of extraction, impregnation, and microcellular scaffold formation was reported for regeneration of bone tissue. A natural antibacterial extract was carried out and purified from Usnea lethariiformis using SC−CO2 extraction, followed by impregnation in the polycaprolactone–hydroxyapatite (PCL–HA) scaffold previously generated using SC−CO2 foaming [118]. At 17 MPa, 35 ◦ C, and reaction time of 3 h, the composite scaffold reached the highest impregnation level of Usnea lethariiformis extract up to 5.9% with scaffold porosity of 50%. This bioactive scaffold showed effective bactericidal activity on methicillin resistant Staphylococcus aureus (MRSA) strains. Porous structure of the PCLHA scaffold is presented in Fig. 14.

3.3.2. The RESS and SAS processes Fine particle formation or microencapsulation using SC−CO2 has been achieved by rapid expansion of a supercritical solution (RESS) [12,14,15,119,120] and antisolvent precipitations, including supercritical antisolvent (SAS) [121–123], particles from gas saturated solutions (PGSS) [124,125], aerosol solvent extraction system (ASES) [88,126], precipitation with compressed anti-solvent (PCA) [127,128], and depressurization of an expanded liquid organic solution (DELOS) [129]. In a RESS process, bioactive compounds and encapsulating polymers are first dissolved in SC−CO2 to form a homogenous SCF solution. Less than 5% colsovents, such as ethanol, can be added to improve the solubility of polar solutes in SC−CO2 [3,5]. During depressurization through a nozzle, rapid expansion of SC−CO2 induces an instability in solubilization of the bioactives and polymers, due to drastic decrease of SC−CO2 density. Microcapsules are produced before aggregation occurs in the rapid RESS process. Microencapsulation of Coenzyme Q10 (coQ10 ) in polyethylene glycol (PEG) or polylactic acid (PLA) using RESS was conducted in SC−CO2 at 27.5 MPa and 35 ◦ C, with ethanol as colsolvent [120]. Depressurized through a 50-␮m I.D. nozzle, the spherical PEG or PLA microcapsules encapsulating coQ10 were generated with the size ranging from 4 to 6 ␮m, as shown in Fig. 15(A). A controlled release rate of coQ10 between 0.06 to 0.09 mg/ml was maintained for 24 h during controlled release study [120]. Antisolvent precipitation is developed to process the compounds with poor solubility in SC−CO2 . This method predominantly utilizes an organic solvent, such as acetone or chloroform, to dissolve bioactives and encapsulating polymers in a homogeneous phase. The homogeneous organic solution is then injected into SC−CO2 under desired operating temperature and pressure. With high diffusivity and low viscosity of SC−CO2 , the organic solution immediately expands, and induces supersaturation of the bioactives and polymers, leading to fast nucleation of microcapsules by rapid mass transfer rate. Polymeric vesicles, composed of polycaprolactone (PCL) and polylactic acid (PLA), were generated using the SAS process to encapsulate and deliver a hormone testosterone, 17␣-methyltestosterone (MT) [130]. The MT-encapsulated microcapsules were produced in SC−CO2 at 8 MPa and 40 ◦ C with PCL/PLA feeding ratio of 1 to 9. The synthesized capsules exhibited the vesicle size ranging from 23 to 54 ␮m and reached encapsulation efficiency of MT up to 50%. First order release kinetics was the best fitted model for the MT controlled release in simulated gastrointestinal conditions within pH values varying from 2.2 to 8.8. Morphology of PCL-PLA microcapsules is presented in Fig. 15(B). 3.3.3. Aerogel formation Aerogels are developed from an initial gel formation in aqueous phase which would then undergo a drying process, such as airdrying or lyophilization. Due to phase destabilization, destruction

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Fig. 15. Formation of polymeric microcapsules in SC−CO2 : (A) Encapsulation of coenzyme Q10 in PLA microcapsules using RESS [120]; (B) Encapsulation of 17␣methyltestosterone in composite PCL/PLA microcapsules generated using SAS [130]. Sources: [120], Copyright 2012. Reproduced with permission from the American Chemical Society; [130], Copyright 2016. Reproduced with permission from Elsevier Ltd.

of polymeric network always occurs during liquid displacement from the porous matrix. Liquid displacement with SC−CO2 drying avoids surface tension, due to absence of liquid to vapor transition, and prevents microcellular network of the hydrogel from further collapse. SC−CO2 drying of certain organogels is specifically practical for acquiring lightweight aerogels that preserve the original porous structure of wet gels, with high specific surface area and porosity of 95 to 99%. Hydrogel of Kappa-carrageenan was synthesized using emulsion polymerization with 1% Span 80 as surfactants and 1% potassium chloride as crosslinking agent [131]. The water in carrageenan hydrogel particles was then gradually replaced with ethanol to form alcogel, followed by SC−CO2 drying at 10 MPa, 60 ◦ C, and a flow rate of 100 g/min. The synthesized aerogel exhibited the surface area varying from 33 to 174 m2 /g, average pore volume of 0.35 ± 0.11 cm3 /g, and average pore size of 12.34 ± 3.24 nm [131]. SC−CO2 drying of ␤-gulcan aerogel with impregnation of acetylsalicylic acid was performed at 9 to 9.5 MPa and 34 ◦ C. The synthesized aerogel exhibited the surface area of 173 to 184 m2 /g, average pore volume of 0.56 to 0.71 cm3 /g, and pore size ranging from 13.7 to 16.1 nm. For acetylsalicylic acid, an optimal loading efficiency at 15% was achieved with moderate in vitro release rate [132]. Morphology of aforementioned polymeric spheres is presented in Fig. 16. 3.3.4. Supercritical emulsion extraction Supercritical emulsion extraction (SEE) integrates conventional emulsion techniques with the unique properties of SC−CO2 to generate the targeted capsules in the size ranging from nano to microscales. The bioactive compound and encapsulating polymer are first dissolved in an organic solvent, followed by addition into aqueous solution to form the oil in water (o/w) emulsion. A nonionic surfactant (HLB value >4) is sometimes required for emulsion stability. Employing SC−CO2 extraction to remove the organic solvent from the o/w emulsion, the bioactive and polymer coprecipitate due to drastic solubility decrease in an aqueous medium, resulting in generation of polymeric capsules. The resultant capsules demonstrate well controlled size and morphology, due to fast mass transfer of the organic solvent into SC−CO2 . Particle agglomeration can be avoided by surfactant-assisted stabilization during initial formation of the o/w emulsion. Microencapsulation of vitamin E in polycaprolactone (PCL) was successfully conducted using SEE [133]. To form the o/w emulsion, PCL and vitamin E were dissolved in acetone and then added into water containing tween 80 as an emulsion stabilizer. The emulsion was treated with SC−CO2 extraction at 8 MPa and 60 ◦ C for 240 min with a CO2 flow rate of 7.2 kg/h. The nanocapsules encapsulating

vitamin E reached an encapsulation efficiency >90% with the vesicle size <300 nm. The morphological analysis indicated a spherical core-and-shell structure of these obtained capsules with storage stability up to 12 months. TEM images of microencapsulated capsules and physicochemical properties are presented in Fig. 17. 3.3.5. Purification and sterilization Biodegradable polymers synthesized using fermentation technique can be separated from bacteria, byproduct oils, and other fermentation residues with SC−CO2 purification. Processing time, cost, and usage of organic solvents would be drastically reduced with this newly developed technique. Poly(␤-hydroxybutyrate) (PHB) were commercially produced by fermentation using different microorganisms, such as Ralstonia eutropha or genetically modified Escherichia coli [134]. The raw PHB was purified with SC−CO2 at 15 MPa, 50 ◦ C for 2 h, and a CO2 flow rate of 2.5 ml/min. Under this optimized condition, 70 wt% of impurities were removed from PHB. SC−CO2 sterilization for biomaterials has been developed as an effective nonthermal alternative with main advantages of nontoxicity, non-inflammability, and minimum microcellular collapse. Complete inactivation of microorganisms would be assured under milder operating conditions in a short processing time [135]. Sterilization of alginate-based membrane was conducted in SC−CO2 at 27 MPa and 40 ◦ C for 3 h, with 200 ppm H2 O2 addition [136]. The mechanical strength and degradation rate of the SC−CO2 sterilized membrane were found to be comparable to the non-sterilized membrane. High biocompatibility of the sterilized membrane was reported based on the in vivo study of porcine intestine surgery. 4. Trends in supercritical fluid technology Supercritical fluid technology is poised to revolutionize pharmaceutical and biomedical engineering. Emerging fields using supercritical SCF technology will be aimed at biodegradable polymer synthesis, fine particle formation, and microencapsulation. Shortened reaction time, milder operating conditions, simplified purification processes, and little to no presence of organic solvents are advantages of SCF technology. Operating cost would be significantly reduced for SCF applications. With tunable density, low viscosity, high diffusivity of SCF, particle size and morphology of the synthesized polymers can be controlled for specific purposes. Synthesis of biodegradable polymers in SC−CO2 can accelerate the reaction rate in milder conditions because high diffusivity of SC−CO2 into reacting matrix for reduced viscosity of the melt. Biocatalysts, such as lipases, can be employed as an ideal substitute for metal-containing catalysts. Porosity of polymeric scaffolds can be adjusted with operating temperature, pressure, and depressurization rate. Morphology and molecular weight can be tailored for fur-

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Fig. 16. SEM images of aerogel formation processed in SC−CO2 with (A) Kappa-carrageenan [131] and (B) ␤-gulcan [132]. Sources: [131], [132], Copyright 2018, 2017, respectively. Reproduced with permission from Elsevier Ltd.

Fig. 17. Microencapsulation of vitamin E in the PCL capsules using supercritical emulsion extraction [133]: (A) TEM image of microencapsulated capsules; (B) Encapsulation efficiency and stability of PCL capsules encapsulating vitamin E during storage for 12 months. Source: [133], Copyright 2017. Reproduced with permission from Elsevier Ltd.

ther applications, such as crosslinking, branching, and dendrimerization for tissue engineering and controlled release of drugs. For drug delivery, the particle size of pharmaceutical compounds can be controlled by depressurization rate of SC−CO2 from micron to nanometer. Bioavailability and solubility of the drugs will be improved to reduce dosage intake. Microencapsulation of bioactive compounds in biodegradable polymeric scaffolds and microcapsules can be conducted in a rapid and continuous process without substantial usage of organic solvents [14,15,100,125], which does not only save the cost of post-treatment, but also can provide pure products to patients who need such medications. Further protection of susceptible compounds, such as growth factors and hormones, by SCF microencapsulation can stabilize drug delivery systems in physiological environment for targeted therapy. The following limitations of SCF technology in polymerization and biomedical applications point to further research opportunities. Hydrophilic compounds with low solubility in SC−CO2 are not suitable for use. Recent effort overcame this by increasing polarity of SC−CO2 with the addition of water or ethanol (<5 wt%) as cosolvents for enhanced dissolution of polar compounds. The challenge in polymerization using SC−CO2 technique is for synthesis of polymers with high crystallinity or high Tg. Increasing diffusivity of SC−CO2 by manipulating operating temperature and pressure can provide a solution to address this challenge. Increasing molecular weight of the product of polycondensation reaction is another challenge in the field because not all polymers can be synthesized

by ring opening polymerizations. As these challenges are resolved, SCF technology will see wider adoptions in polymer research and production.

5. Conclusions Supercritical fluid technology in polymerization provides a milder and ecofriendly alternative for polymer synthesis. Use of organic solvents would be drastically reduced or completely avoided. Concomitantly, lipase-catalyzed polymerization successfully conducted in SC−CO2 can reduce the reliance on metal catalysts in polymer synthesis. Microcapsule formation, microcellular scaffold fabrication, and bioactive coatings with SC−CO2 polymerization provide property−COntrolled strategies for related biomedical applications, such as drug delivery, tissue engineering, and biocompatible implant development. Tremendous progress in SC−CO2 polymerization has been made in the last decade. Moving forward, scale-up and continuous process design are needed for industrial applications of SC−CO2 polymerization.

Acknowledgement The authors acknowledge financial support from Cornell Startup Fund by Cornell University.

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References [1] Zhang J, Yang S, Yang X, Xi Z, Zhao L, Cen L, et al. Novel fabricating process for porous polyglycolic acid scaffolds by melt-foaming using supercritical carbon dioxide. ACS Biomater Sci Eng 2018;4:694–706. [2] Ngo TT, Blair S, Kuwahara K, Christensen D, Barrer I, Domingo M, et al. Drug impregnation for laser sintered poly(methyl methacrylate) biocomposites using supercritical carbon dioxide. J Supercrit Fluids 2018;136:29–36. [3] Tsai WC, Rizvi SSH. Liposomal microencapsulation using the conventional methods and novel supercritical fluid processes. Trends Food Sci Technol 2016;55:61–71. [4] Rizvi SSH, Benado AL, Zollweg JA, Daniels JA. Supercritical fluid extraction: fundamental principles and modelling methods. Food Technol 1986;40:55–65. [5] Tsai WC, Ruan Y, Rizvi SSH. Solubility measurement of methyl anthranilate in supercritical carbon dioxide using dynamic and static equilibrium systems. J Environ Sci Health B 2006;86:2083–91. [6] Tsai WC, Rizvi SSH. Measurement and correlation of citronellal and methyl anthranilate solubilities in supercritical carbon dioxide. J Chem Eng Data 2016;61:182–7. [7] Couto R, Seifried B, Moquin P, Temelli F. Coenzyme Q10 solubility in supercritical CO2 using a dynamic system. J CO2 Util 2018;24:315–20. [8] Pal S, Bhattacharjee P. Spray dried powder of lutein-rich supercritical carbon dioxide extract of gamma-irradiated marigold flowers: process optimization, characterization and food application. Powder Technol 2018;327:512–23. [9] Vieitez I, Maceiras L, Jachmanián I, Alborés S. Antioxidant and antibacterial activity of different extracts from herbs obtained by maceration or supercritical technology. J Supercrit Fluids 2018;133:58–64. [10] Ouédraogo JCW, Dicko C, Kini F, Bonzi-Coulibaly YL, Dey ES. Enhanced extraction of flavonoids from Odontonema strictum leaves with antioxidant activity using supercritical carbon dioxide fluid combined with ethanol. J Supercrit Fluids 2018;131:66–71. [11] Xu A, Lu Q, Huo Z, Ma J, Geng B, Azhar U, et al. Synthesis of fluorinated nanoparticles via RAFT dispersion polymerization-induced self-assembly using fluorinated macro-RAFT agents in supercritical carbon dioxide. RSC Adv 2017;7:51612–20. [12] Wolff S, Beuermann S, Türk M. Impact of rapid expansion of supercritical solution process conditions on the crystallinity of poly(vinylidene fluoride) nanoparticles. J Supercrit Fluids 2016;117:18–25. [13] Zhou Y, Du J, Wang L, Wang Y. State of the art of nanocrystals technology for delivery of poorly soluble drugs. J Nanopart Res 2016;18, 257/1-22. [14] Tsai WC, Rizvi SSH. Simultaneous microencapsulation of hydrophilic and lipophilic bioactives in liposomes produced by an ecofriendly supercritical fluid process. Food Res Int 2017;99:256–62. [15] Tsai WC, Rizvi SSH. Microencapsulation and characterization of liposomal vesicles using a supercritical fluid process coupled with vacuum-driven cargo loading. Food Res Int 2017;96:94–102. [16] Zhao H. Enzymatic ring-opening polymerization (ROP) of polylactones: roles of non-aqueous solvents. J Chem Technol Biot 2018;93:9–19. [17] Badgujar KC, Bhanage BM. Immobilization of lipase on biocompatible co-polymer of polyvinyl alcohol and chitosan for synthesis of laurate compounds in supercritical carbon dioxide using response surface methodology. Process Biochem 2015;50:1224–36. [18] More SB, Waghmare JS, Gogate PR, Naik SN. Improved synthesis of medium chain triacylglycerol catalyzed by lipase based on use of supercritical carbon dioxide pretreatment. Chem Eng J 2018;334:1977–87. [19] Chrastil J. Solubility of solids and liquids in supercritical gases. J Phys Chem 1982;86:3016–21. [20] Rebelatto EA, Bender JP, Corazza ML, Ferreira SRS, Oliveira JV, Lanza M. High-pressure phase equilibrium data for the (carbon dioxide+L-lactide+ethanol) system. J Chem Thermodyn 2015;86:37–42. [21] Rebelatto EA, Polloni AE, Andrade KS, Bender JP, Corazza ML, Lanza M, et al. High-pressure phase equilibrium data for systems containing carbon dioxide, ␻-pentadecalactone, chloroform and water. J Chem Thermodyn 2018;122:125–32. [22] Hua H, Zhang R, Wang J, Ying WB, Zhu J. Fully bio-based poly(propylene succinate-co-propylene furandicarboxylate) copolyesters with proper mechanical, degradation and barrier properties for green packaging applications. Eur Polym J 2018;102:101–10. [23] Xu J, Qin B, Luan S, Qi P, Wang Y, Wang K, et al. Acid-labile poly(ethylene glycol) shell of hydrazone-containing biodegradable polymeric micelles facilitating anticancer drug delivery. J Bioact Compat Polym 2018;33:119–33. [24] Madhavan K, Frid MG, Hunter K, Shandas R, Stenmark KR, Park D. Development of an electrospun biomimetic polyurea scaffold suitable for vascular grafting. J Biomed Mater Res Part B Appl Biomater 2017;106B:278–90. [25] Coulembier O, Degee´ P, Hedrick JL, Dubois P. From controlled ring-opening polymerization to biodegradable aliphatic polyester: especially poly(b-malic acid) derivatives. Prog Polym Sci 2006;31:723–47. [26] Wang Y, Ameer GA, Sheppard BJ, Langer R. A tough biodegradable elastomer. Nat Biotechnol 2002;20:602–6. [27] Jeffries EM, Allen RA, Gao J, Pesce M, Wang Y. Highly elastic and suturable electrospun poly(glycerol sebacate) fibrous scaffolds. Acta Biomater 2015;18:30–9.

[28] Secret E, Crannell KE, Kelly SJ, Villancio-Wolter M, Andrew JS. Matrix metalloproteinase-sensitive hydrogel microparticles for pulmonary drug delivery of small molecule drugs or proteins. J Mater Chem B Mater Biol Med 2015;3:5629–34. [29] Zaks A, Klibanov AM. Enzymatic catalysis in organic media at 100 oC. Science 1984;224:1249–51. [30] Zaks A, Klibanov AM. Enzyme-catalyzed processes in organic solvents. Proc Natl Acad Sci USA 1985;82:3192–6. [31] Cheng HN, Gu QM. Enzyme-catalyzed modifications of polysaccharides and poly(ethylene glycol). Polymers 2012;4:1311–30. ˜ [32] Japu C, Ilarduya AMd, Alla A, Jiang Y, Munoz-Guerra KL. Copolyesters made from 1,4-Butanediol, sebacic acid, and D-Glucose by melt and enzymatic polycondensation. Biomacromolecules 2015;16:868–79. [33] Wu W, Qu L, Liu B, Zhang W, Wang N, Yu X. Lipase-catalyzed synthesis of acid-degradable poly(␤-thioether ester) and poly(␤-thioether ester-co-lactone) copolymers. Polym Chem 2015;59:187–93. [34] Polloni AE, Veneral JG, Rebelatto EA, Dd Oliveira, Oliveira JV, Araújo PHH, et al. Enzymatic ring opening polymerization of ␻-pentadecalactone using supercritical carbon dioxide. J Supercrit Fluids 2017;119:221–8. [35] Cipolatti EP, Valério A, Ninow J L, Oliveira D, Pessela BC. Stabilization of lipase from Thermomyces lanuginosus by crosslinking in PEGylated polyurethane particles by polymerization: application on fish oil ethanolysis. Biochem Eng J 2016;112:54–60. [36] Xu L, Ke C, Huang Y, Yan Y. Immobilized Aspergillus niger lipase with SiO2 nanoparticles in sol-gel materials. Catalysts 2016;6, 149/1-12. [37] Badgujar VC, Badgujar KC, Yeole PM, Bhanage BM. Immobilization of Rhizomucor miehei lipase on a polymeric film for synthesis of important fatty acid esters: kinetics and application studies. Bioprocess Biosyst Eng 2017;40:1463–78. [38] Nalder TD, Kurtovic I, Barrow CJ, Marshall SN. A simplified method for active-site titration of lipases immobilised on hydrophobic supports. Enzyme Microb Technol 2018;113:18–23. [39] Badgujar KC, Bhanage BM. Investigation of deactivation thermodynamics of lipase immobilized on polymeric carrier. Bioprocess Biosyst Eng 2017;40:741–57. [40] Gebhard J, Neuer B, Luinstra GA, Liese A. Enzyme- and metal-catalyzed synthesis of a new biobased polyester. Org Process Res Dev 2017;21:1245–52. [41] Hiroshi U, Shiro K. Enzymatic ring-opening polymerization of lactones catalyzed by lipase. Chem Lett 1993;22:1149–50. [42] Deng J, Zhan S, Wang J, Liu Z, Li Z. Ring-opening dispersion polymerization of L-lactide with polylactide stabilizer in supercritical carbon dioxide. Aust J Chem 2017;70:712–7. [43] Uyama H, Inada K, Kobayashi S. Regioselectivity control in lipase-catalyzed polymerization of divinyl sebacate and triols. Macromol Biosci 2001;1:40–4. [44] Dubois J, Grau E, Tassaing T, Dumon M. On the CO2 sorption and swelling of elastomers by supercritical CO2 as studied by in situ high pressure FTIR microscopy. J Supercrit Fluids 2018;131:150–6. [45] Guindani C, Dozoretz P, Veneral JG, DMd Silva, Araújo PHH, Ferreira SRS, et al. Enzymatic ring opening copolymerization of globalide and ␧-caprolactone under supercritical conditions. J Supercrit Fluids 2017;128:404–11. [46] Kunita MH, Rinaldi AW, Girotto EM, Radovanovic E, Muniz EC, Rubira AF. Grafting of glycidyl methacrylate onto polypropylene using supercritical carbon dioxide. Eur Polym J 2005;41:2176–82. [47] Bochona I, Karethb S, Kilzer A, Petermann M. Synthesis and powder generation of powder coatings using supercritical carbon dioxide. J Supercrit Fluids 2015;96:324–33. [48] Tainio J, Paakinaho K, Ahola N, Hannula M, Hyttinen J, Kellomäki M, et al. In vitro degradation of borosilicate bioactive glass and poly(L-lactide-co-␧-caprolactone) composite scaffolds. Materials 2017;10(1274):1–13. [49] Xia T, Feng Y, Zhang Y, Xi Z, Liu T, Zhao L. Poly(glycerol sebacate)-modified polylactic acid scaffolds with improved hydrophilicity, mechanical strength and bioactivity for bone tissue regeneration. RSC Adv 2015;5:79703–14. [50] Jia Y, Wang W, Zhou X, Nie W, Chen L, He C. Synthesis and characterization of poly(glycerol sebacate)-based elastomeric copolyesters for tissue engineering applications. Polym Chem 2016;7:2553–64. [51] Galy N, Nguyen R, Yalgin H, Thiebault N, Luart D, Len C. Glycerol in subcritical and supercritical solvents. J Chem Technol Biot 2017;92:14–26. [52] Belomoina NM, Bulycheva EG, Elmanovich IV, Buzin MI, Begunov RS, Chaschin IS, et al. Supercritical carbon dioxide as an effective medium for poly(naphthoylenebenzimidazole)’s synthesis. J Supercrit Fluids 2019;148:148–54. [53] Zhong H, Xi Z, Liu T, Xu Z, Zhao L. Integrated process of supercritical CO2-assisted melt polycondensation modification and foaming of poly(ethylene terephthalate). J Supercrit Fluids 2013;74:70–9. [54] Börner J, Vieira IDS, Pawlis A, Döring A, Kuckling D, Herres-Pawlis S. Mechanism of the living lactide polymerization mediated by robust zinc guanidine complexes. Chem Eur J 2011;17:4507–12. [55] Jérôme C, Lecomte P. Recent advances in the synthesis of aliphatic polyesters by ring-opening polymerization. Adv Drug Deliv Rev 2008;60:1056–76. [56] Goddard AR, Pérez-Nieto S, Passos TM, Quilty B, Carmichael K, Irvine DJ, et al. Controlled polymerisation and purification of branched poly(lactic acid) surfactants in supercritical carbon dioxide. Green Chem 2016;18: 4772–86.

W.-C. Tsai and Y. Wang / Progress in Polymer Science 98 (2019) 101161 [57] Linko YY, Lämsä M, Wu X, Uosukainen E, Seppälä J, Linkoa P. Biodegradable products by lipase biocatalysis. J Biotechnol 1998;66:41–50. [58] Omay D, Guvenilir Y. Synthesis and characterization of poly(d,l-lactic acid) via enzymatic ring opening polymerization by using free and immobilized lipase. Biocatal Biotransformation 2013;31:132–40. [59] Curia S, Barclay AF, Torron S, Johansson M, Howdle SM. Green process for green materials: viable low-temperature lipase-catalysed synthesis of renewable telechelics in supercritical CO2. Philos Trans Math Phys Eng Sci 2015;373, 20150073/1-16. [60] Knani D, Gutman AL, Kohn DH. Enzymatic polyesterification in organic media. Enzyme-catalyzed synthesis of linear polyesters. I. Condensation polymerization of linear hydroxyesters. II. Ring-opening polymerization of ␧-caprolactone. J Polym Sci Part A: Polym Chem 1993;31:1221–32. [61] Xia T, Feng Y, Zhan Y, Xi Z, Liu T, Zhao L. Novel strategy for polycondensation of poly(ethylene terephthalate) assisted by supercritical carbon dioxide. Ind Eng Chem Res 2014;53:18194–201. [62] Yang Y, Lu W, Cai J, Hou Y, Ouyang S, Xie W, et al. Poly(oleic diacid-co-glycerol): comparison of polymer structure resulting from chemical and lipase catalysis. Macromolecules 2011;44:1977–85. [63] Ding Y, Ni X, Gu M, Li S, Huang H, Hu Y. Knoevenagel condensation of aromatic aldehydes with active methylene compounds catalyzed by lipoprotein lipase. Catal Commun 2015;64:101–4. [64] He W, Lan J, Huang X, Shang J. Synthesis, characterization, and properties of biodegradable poly(butylene succinate) modified with imide dihydric alcohol. J Appl Polym Sci 2014;131:9579–85. [65] Kobayashi S. Lipase-catalyzed polyester synthesis – a green polymer chemistry. Proc Jpn Acad, Ser B, Phys Biol Sci 2010;86:338–65. [66] Marty A, Chulalaksananukul W, Condoret JS, Willemot RM, Durand G. Comparison of lipase-catalysed esterification in supercritical carbon dioxide and in n-hexane. Biotechnol Lett 1990;12:11–6. [67] Varma MN, Madras G. Effect of chain length of alcohol on the lipase-catalyzed esterification of propionic acid in supercritical carbon dioxide. Appl Biochem Biotechnol 2010;160:2342–54. [68] Rauwerdink A, Kazlauskas RJ. How the same core catalytic machinery catalyzes 17 different reactions: the serine-histidine-aspartate catalytic triad of ␣/␤-hydrolase fold enzymes. ACS Catal 2015;5:6153–76. [69] Kobayashi S. New developments of polysaccharide synthesis via enzymatic polymerization. Proc Jpn Acad, Ser B, Phys Biol Sci 2007;83:215–47. [70] Ardhaoui M, Falcimaigne A, Engasser JM, Moussou P, Pauly G, Ghoul M. Enzymatic synthesis of new aromatic and alipathic esters of flavonoids using Candida antarctica lipase as biocatalyst. Biocatal Biotransformation 2004;22:253–9. [71] Jiang Y, Loos K. Enzymatic synthesis of biobased polyesters and polyamides. Polymers 2016;8, 243/1-53. [72] Santini S, Crowet JM, Thomas A, Paquot M, Vandenbol M, Thonart P, et al. Study of thermomyces lanuginosa lipase in the presence of tributyrylglycerol and water. Biophys J 2009;96:4814–25. [73] Thurecht KJ, Heise A, deGeus M, Villarroya S, Zhou J, Wyatt MF, et al. Kinetics of enzymatic ring-opening polymerization of ␧-caprolactone in supercritical carbon dioxide. Macromolecules 2006;39:7967–72. [74] Polloni AE, Chiaradia V, Figura EM, Paoli JPD, Dd Oliveira, JVd Oliveira, et al. Polyesters from macrolactones using commercial lipase NS 88011 and Novozym 435 as biocatalysts. Appl Biochem Biotechnol 2018;184:659–72. ˜ [75] Morales-Huerta JC, Ciulik CB, AMd Ilarduya, Munoz-Guerra S. Fully bio-based aromatic–aliphatic copolyesters: poly(butylene furandicarboxylate-co-succinate)s obtained by ring opening polymerization. Polym Chem 2017;8:748–60. [76] Nicolás P, Lassalle V, Ferreira ML. Immobilization of CALB on lysine-modified magnetic nanoparticles: influence of the immobilization protocol. Bioprocess Biosyst Eng 2018;41:171–84. [77] Zhang C, Dong X, Guo Z, Sun Y. Remarkably enhanced activity and substrate affinity of lipase covalently bonded on zwitterionic polymer-grafted silica nanoparticles. J Colloid Interface Sci 2018;591:145–53. [78] Rosso SRC, Bianchin E, Dd Oliveira, Oliveira JV, Ferreira SRS. Enzymatic synthesis of poly(␧-caprolactone) in supercritical carbon dioxide medium by means of a variable-volume view reactor. J Supercrit Fluids 2013;79:133–41. [79] Salerno A, Domingoa C. Polycaprolactone foams prepared by supercritical CO2 batch foaming of polymer/organic solvent solutions. J Supercrit Fluids 2019;143:146–56. [80] García-Arrazola R, López-Guerrero DA, Gimeno M, Bárzana E. Lipase-catalyzed synthesis of poly-L-lactide using supercritical carbon dioxide. J Supercrit Fluids 2009;51:197–201. [81] Chen AZ, Tang N, Wang SB, Kang YQ, Song HF. Insulin-loaded poly-l-lactide porous microspheres prepared in supercritical CO2 for pulmonary drug delivery. J Supercrit Fluids 2015;101:117–23. [82] Du L, Kelly JY, Roberts GW, DeSimone JM. Fluoropolymer synthesis in supercritical carbon dioxide. J Supercrit Fluids 2009;47:447–57. [83] Ahmed TS, DeSimone JM, Roberts GW. Copolymerization of vinylidene fluoride with hexafluoropropylene in supercritical carbon dioxide. Macromolecules 2006;39:15–8. [84] Beuermann S, Imran-Ul-Haq M. Homogeneous phase polymerization of vinylidene fluoride in supercritical carbon dioxide. J Polym Sci Part A: Polym Chem 2007;45:5626–35. [85] Kermagoret A, Chau NDQ, Grignard B, Cordella D, Debuigne A, Jérôme C, et al. Cobalt-mediated radical polymerization of vinyl acetate and acrylonitrile in supercritical carbon dioxide. Macromol Rapid Commun 2016;37:539–44.

17

[86] Shieh YT, Chen BH. Effect of carbon nanotubes on free radical polymerization of N-isopropylacrylamide in supercritical carbon dioxide and in methanol. J Supercrit Fluids 2016;107:624–9. [87] Kwon S, Bae W, Kim H. The effect of CO2 in free-radical polymerization of 2,2,2-trifluoroethyl methacrylate. Korean J Chem Eng 2004;21:910–4. [88] Kwon S, Lee K, Bae W, Kim H. Precipitation polymerization of 2-methylene-1,3-dioxepane in supercritical carbon dioxide. Polym J 2008;40:332–8. [89] Arshady R. Suspension, emulsion, and dispersion polymerization: a methodological survey. Colloid Polym Sci 1992;270:717–32. [90] Shiho H, DeSimone JM. Dispersion polymerization of acrylonitrile in supercritical carbon dioxide. Macromolecules 2000;33:1565–9. [91] Woods HM, Nouvel C, Licence P, Irvine DJ, Howdle SM. Dispersion polymerization of methyl methacrylate in supercritical carbon dioxide: an investigation into stabilizer anchor group. Macromolecules 2005;38:3271–82. [92] Haruki M, Kodama Y, Tachimori K, Kihara SI, Takishima S. Dispersion polymerization of methyl methacrylate with three types of comblike fluorinated stabilizers in supercritical carbon dioxide. J Appl Polym Sci 2016;133, 43813/1-10. [93] Alaimo D, Grignard B, Kuppan C, Adriaensen Y, Genet MJ, Dupont-Gillain C, et al. A photocleavable stabilizer for the preparation of PHEMA nanogels by dispersion polymerization in supercritical carbon dioxide. Polym Chem 2017;8:581–91. [94] Wang T, Ding J, Zhao X, Liu Y, Hao J. Suspension polymerization of poly(L-lactide-co-p-dioxanone) in supercritical carbon dioxide. J Polym Environ 2012;20:157–63. [95] Hussain YA, Liu T, Roberts GW. Synthesis of cross-linked, partially neutralized poly(acrylic acid) by suspension polymerization in supercritical carbon dioxide. Ind Eng Chem Res 2012;51:11401–8. [96] Jennings J, Beija M, Richez AP, Cooper SD, Mignot PE, Thurecht KJ, et al. One-pot synthesis of block copolymers in supercritical carbon dioxide: a simple versatile route to nanostructured microparticles. J Am Chem Soc 2012;134:4772–81. [97] He G, Bennett TM, Alauhdin M, Fay MW, Liu X, Schwab ST, et al. A facile route to bespoke macro- and mesoporous block copolymer microparticles. Polym Chem 2018;9:3808–19. [98] Jaramillo-Soto G, Vivaldo-Lima E. RAFT copolymerization of styrene/divinylbenzene in supercritical carbon dioxide. Aust J Chem 2012;65:1177–85. [99] Jaramillo-Soto G, Villa-Ávila CM, Vivaldo-Lima E. RAFT copolymerization with crosslinking of methyl methacrylate and ethylene glycol dimethacrylate in supercritical carbon dioxide. J Macromol Sci A 2013;50:281–6. [100] Nerantzaki M, Skoufa E, Adam KV, Nanaki S, Avgeropoulos A, Kostoglou M, et al. Amphiphilic block copolymer microspheres derived from castor oil, poly(␧-carpolactone), and poly(ethylene glycol): preparation, characterization and application in naltrexone drug delivery. Materials 2018;11, 1996/1-19. [101] Chun H, Yeom M, Kim HO, Lim JW, Na W, Park G, et al. Efficient antiviral co-delivery using polymersomes by controlling the surface density of cell-targeting groups for influenza A virus treatment. Polym Chem 2018;9:2116–23. [102] Curia S, Howdle SM. Towards sustainable polymeric nano-carriers and surfactants: facile low temperature enzymatic synthesis of bio-based amphiphilic copolymers in scCO2. Polym Chem 2016;7:2130–42. [103] Parilti R, Caprasse J, Riva R, Alexandre M, Vandegaart H, Bebrone C, et al. Antimicrobial peptide encapsulation and sustained release from polymer network particles prepared in supercritical carbon dioxide. J Colloid Interface Sci 2018;532:112–7. [104] Parilti R, Riva R, Howdle S M, Dupont-Gillainc C, Jerome C. Sulindac encapsulation and release from functional poly(HEMA)microparticles prepared in supercritical carbon dioxide. Int J Pharm 2018;549: 161–8. [105] Hao Y, Zhao J, Wang G, Cao L, Wang J, Yue F. Grafting of thermo- and pH-responsive polymer inside mesoporous silica foam in supercritical carbon dioxide for controlled release of 5-fluorouracil. Fiber Polym 2017;18:2476–80. [106] Cooper AI. Polymer synthesis and processing using supercritical carbon dioxide. J Mater Chem 2000;10:207–34. [107] Santo VE, Duarte ARC, Popa EG, Gomes ME, Mano JF, Reis RL. Enhancement of osteogenic differentiation of human adipose derived stem cells by the controlled release of platelet lysates from hybrid scaffolds produced by supercritical fluid foaming. J Control Release 2012;162:19–27. [108] Cooper AI. Porous materials and supercritical fluids. Adv Mater 2003;15:1049–59. ˜ B, [109] Salerno A, Diéguez S, Diaz-Gomez L, Gómez-Amoza JL, Magarinos Concheiro A, et al. Synthetic scaffolds with full pore interconnectivity for bone regeneration prepared by supercritical foaming using advanced biofunctional plasticizers. Biofabrication 2017;9, 035002/1-16. [110] Wang X, Salick MR, Gao Y, Jiang J, Li X, Liu F, et al. Interconnected porous poly(␧-caprolactone) tissue engineering scaffolds fabricated by microcellular injection molding. J Cell Plast 2018;54:379–97. [111] Xin X, Guan YX, Yao SJ. Sustained release of dexamethasone from drug-loading PLGA scaffolds with specific pore structure fabricated by supercritical CO2 foaming. J Appl Polym Sci 2018;135, 46207/1-7.

18

W.-C. Tsai and Y. Wang / Progress in Polymer Science 98 (2019) 101161

[112] Salernoa A, Saurinab J, Domingoa C. Supercritical CO2 foamed polycaprolactone scaffolds for controlled delivery of 5-fluorouracil, nicotinamide and triflusal. Int J Pharm 2015;496:654–63. [113] Salimia K, Yilmaza M, Rzayeva ZMO, Piskina E. Controlled graft copolymerization of lactic acid onto starch in a supercritical carbon dioxide medium. Carbohydr Polym 2014;114:149–56. [114] Hokugo A, Ozeki M, Kawakami O, Sugimoto K, Mushimoto K, Morita S, et al. Augmented bone regeneration activity of platelet-rich plasma by biodegradable gelatin hydrogel. Tissue Eng 2005;11:1224–33. [115] Diaz-Gomez L, Concheiro A, Alvarez-Lorenzo C, García-González CA. Growth factors delivery from hybrid PCL-starch scaffolds processed using supercritical fluid technology. Carbohydr Polym 2016;142:282–92. [116] Matsuyama H, Yamamoto A, Yano H, Maki T, Teramoto M, Mishim K, et al. Effect of organic solvents on membrane formation by phase separation with supercritical CO2. J Membrane Sci 2002;204:81–7. [117] Deng A, Chen A, Wang S, Li Y, Liu Y, Cheng X, et al. Porous nanostructured poly-L-lactide scaffolds prepared by phase inversion using supercritical CO2 as a nonsolvent in the presence of ammonium bicarbonate particles. J Supercrit Fluids 2013;77:110–6. [118] Fanovich MA, Ivanovic J, Zizovic I, Misic D, Jaeger P. Functionalization of polycaprolactone/hydroxyapatite scaffolds with Usnea lethariiformis extract by using supercritical CO2. Mater Sci Eng C 2016;58:204–12. [119] Ratcharaka O, Sane A. Surface coating with poly(trifluoroethyl methacrylate) through rapid expansion of supercritical CO2 solutions. J Supercrit Fluids 2014;89:106–12. [120] Vergara-Mendoza Md S, Ortiz-Estrada CH, González-Martínez J, Quezada-Gallo JA. Microencapsulation of coenzyme Q10 in poly(ethylene glycol) and poly(lactic acid) with supercritical carbon dioxide. Ind Eng Chem Res 2012;51:5840–6. [121] Janiszewska-Turak E. Carotenoids microencapsulation by spray drying method and supercritical micronization. Food Res Int 2017;99:891–901. [122] Chhouk K, Wahyudiono Kanda H, Kawasaki SI, Goto M. Micronization of curcumin with biodegradable polymer by supercritical anti-solvent using micro swirl mixer. Front Chem Sci Eng 2018;12:184–93. [123] Alias D, Yunus R, Chong GH, Abdullah CAC. Single step encapsulation process of tamoxifen in biodegradable polymer using supercritical anti-solvent (SAS) process. Powder Technol 2017;309:89–94. [124] Perinelli DR, Bonacucina G, Cespia M, Naylor A, Whitaker M, Palmieri GF, et al. Evaluation of P(L)LA-PEG-P(L)LA as processing aid for biodegradable particles from gas saturated solutions (PGSS) process. Int J Pharm 2014;468:250–7. [125] Jordan F, Naylor A, Kelly CA, Howdle SM, Lewis A, Illum L. Sustained release hGH microsphere formulation produced by a novel supercritical fluid technology: in vivo studies. J Control Release 2010;141:153–60. [126] Tandya A, Zhuang HQ, Mammucari R, Foster NR. Supercritical fluid micronization techniques for gastroresistant insulin formulations. J Supercrit Fluids 2016;107:9–16. [127] Marco ID, Rossmann M, Prosapio V, Reverchon E, Braeuer A. Control of particle size, at micrometric and nanometric range, using supercritical antisolvent precipitation from solvent mixtures: application to PVP. Chem Eng J 2015;273:344–52. [128] Prosapio V, Marco ID, Reverchon E. PVP/corticosteroid microspheres produced by supercritical antisolvent coprecipitation. Chem Eng J 2016;292:264–75. [129] Moreno-Calvo E, Temelli F, Cordoba A, Masciocchi N, Veciana J, Ventosa N. A new microcrystalline phytosterol polymorph generated using CO2-expanded solvents. Cryst Growth Des 2014;14:58–68. [130] Sacchetin PSC, Setti RF, PdTV e Rosa, Moraes ÂM. Properties of PLA/PCL particles as vehicles for oral delivery of the androgen hormone 17␣-methyltestosterone. Mater Sci Eng C 2016;58:870–81. [131] Alnaief M, Obaidat R, Mashaqbeh H. Effect of processing parameters on preparation of carrageenan aerogel microparticles. Carbohydr Polym 2018;180:264–75. [132] Salgado M, Santos F, Rodríguez-Rojo S, Reis RL, Duarte ARC, Cocero MJ. Development of barley and yeast ␤-glucan aerogels for drug delivery by supercritical fluids. J CO2 Util 2017;22:262–9.

[133] Prieto C, Calvo L. Supercritical fluid extraction of emulsions to nanoencapsulate vitamin E in polycaprolactone. J Supercrit Fluids 2017;119:274–82. [134] Daly SR, Fathia A, Bahramian B, Manavitehrani I, McClure DD, Valtchev P, et al. A green process for the purification of biodegradable poly(␤-hydroxybutyrate). J Supercrit Fluids 2018;135:84–90. [135] Lanzalaco S, Campora S, Brucato V, Pavia FC, Leonardo ERD, Ghersi G, et al. Sterilization of macroscopic poly(l-lactic acid) porous scaffolds with dense carbon dioxide: investigation of the spatial penetration of the treatment and of its effect on the properties of the matrix. J Supercrit Fluids 2016;111:83–90. [136] Scognamiglio F, Blanchy M, Borgogna M, Travan A, Donati I, JWAM Bosmans, et al. Effects of supercritical carbon dioxide sterilization on polysaccharidic membranes for surgical applications. Carbohydr Polym 2017;173:482–8. [137] Ye H, Owh C, Jiang S, Ng CZQ, Wirawan D, Loh XJ. A thixotropic polyglycerol sebacate-based supramolecular hydrogel as an injectable drug delivery matrix. Polymers 2016;8, 130/1-15. [138] Reano AF, Domenek S, Pernes M, Beaugrand J, Allais F. Ferulic acid-based bis/trisphenols as renewable antioxidants for polypropylene and poly(butylene succinate). ACS Sustain Chem Eng 2016;4:6562–71. [139] Díaz A, Franco L, Estrany F, Valle LJD, Puiggalí J. Poly(butylene azelate-co-butylene succinate) copolymers: crystalline morphologies and degradation. Polym Degrad Stab 2014;99:80–91. [140] Cîrcu M, Bunge A, Vasilescu C, Porav S, Nan A. Non-catalytic, solvent-free synthesisof poly(tartronic-co-glycolic acid) as a versatilecoating for diff ;erent surfaces. Polym Int 2018;67:212–9. [141] Jia Z, Wang J, Sun L, Zhu J, Liu X. Fully bio-based polyesters derived from 2,5-furandicarboxylic acid(2,5-FDCA) and dodecanedioic acid (DDCA): from semicrystallinethermoplastic to amorphous elastomer. J Appl Polym Sci 2018;135, 46076/1-11. [142] Lu J, Wu L, Li BG. High molecular weight polyesters derived from biobased 1,5-pentanediol and a variety of aliphatic diacids: synthesis, characterization, and thermo-mechanical properties. ACS Sustain Chem Eng 2017;5:6159–66. [143] Kleopas A, Picchioni SF, Heeres HJ. Experimental studies on the ring opening polymerization of p-dioxanone using an Al(OiPr)3-monosaccharide initiator system. Eur Polym J 2009;45:155–64. [144] Zhao N, Ren C, Li H, Li Y, Liu S, Li Z. Selective ring-opening polymerization of non-strained g-butyrolactone catalyzed by a cyclic trimeric phosphazene base. Angew Chem Int Ed 2017;56:12987–90. [145] Hu Z, Chen Y, Huang H, Liu L, Chen Y. Well-defined poly(␣-amino-ı-valerolactone) via living ring-opening polymerization. Macromolecules 2018;51:2526–32. [146] Liu J, Ji X, Zhao H. Block copolymer micelles with enzyme molecules at the interfaces. J Polym Sci Part A: Polym Chem 2017;55:2047–52. [147] Sobczak M. Enzyme-catalyzed ring-opening polymerization of cyclic esters in the presence of poly(ethylene glycol). J Appl Polym Sci 2012;125:3602–9. [148] Vassiliadi E, Xenakis A, Zoumpanioti M. Chitosan hydrogels: a new and simple matrix for lipase catalysed biosyntheses. Mol Catal 2018;445:206–12. [149] Pfluck ACD, DPCd Barros, LıP Fonseca, Melo EP. Stability of lipases in miniemulsion systems: correlation between secondary structure and activity. Enzyme Microb Technol 2018;114:7–14. [150] Rahmayetty S, Prasetya B, Gozan M. Synthesis and characterization of L-lactide and polylactic acid (PLA) from L-lactic acid for biomedical applications. AIP Conf Proc 2017;1817, 020009/1-10. [151] Cipolatti EP, Moreno-Pérez S, LTdA Souza, Valério A, Guisán J M, deAraújo PHH, et al. Synthesis and modification of polyurethane for immobilization of Thermomyces lanuginosus (TLL) lipase for ethanolysis of fish oil in solvent free system. J Mol Catal, B Enzym 2015;122:163–9. [152] Khan FI, Lan D, Durrani R, Huan W, Zhao Z, Wang Y. The lid domain in lipases: structural and functional determinant of enzymatic properties. Front Bioeng Biotechnol 2017;5, 16/1-13. [153] Kokkinou M, Theodorou LG, Papamichael EM. Aspects on the catalysis of lipase from porcine pancreas (type VI-s) in aqueous media: development of ion-pairs. Braz Arch Biol Technol 2012;55:213–6.