The polymerization of carbon dioxide (CO₂) with epoxides to form polycarbonate can maximize the use of CO₂ to achieve value-adding benefits, in which polycarbonate has great potential for biomedical applications due to its excellent optical and mechanical properties, as well as good biocompatibility (Paul et al., 2015b; Cui et al., 2019; Ye et al., 2019). Compared with petroleum derivative monomers, bio-based monomers usually have more functional groups, and it is difficult to achieve highly selective polymerization through traditional polymerization methods (Stadler et al., 2019). For ring-opening copolymerization (ROCOP) of epoxide with CO₂ or cyclic anhydrides, many efficient metal-based catalysts have been developed to produce alternating polycarbonates or polyesters (Paul et al., 2015b; Longo et al., 2016; Xia and Zhao, 2018; Liang et al., 2021), including zinc (Deacy et al., 2018, 2020a; Denk et al., 2020), cobalt (Li et al., 2017a; Ambrose et al., 2019), aluminum (Sanford et al., 2018), or nickel (Huang et al., 2017; Li et al., 2017a) complexes with different ligands. These organometallic catalysts exhibit excellent catalytic performance and high selectivity toward the formation of ester or carbonate linkages during polymerizations, showing reduced side reactions forming ether linkages or cyclic carbonates. In recent years, dinuclear metal catalysts have received widespread attention due to their higher catalytic efficiency than mononuclear catalysts (Yu et al., 2016; Garden et al., 2017), due to the synergy between metals (Cheng et al., 2019). Besides, many studies have shown that dinuclear catalysts usually showed an excellent catalytic activity even in the absence of cocatalysts (Kember and Williams, 2012; Saini et al., 2014). Dinuclear metal catalysts generally exhibited a higher catalytic activity and selectivities as well as fewer side reactions, which could be advantageous for making biopolymers with well-defined chain structures.

Despite the fact that metal-based catalysts have shown excellent catalytic performance, there are also some problems such as complicated ligand design and synthesis procedure in order to reach high catalytic ability (Saini et al., 2014). In addition, the removal of residual metal substances in the system after the polymerization is also a problem that needs attention (Alferov et al., 2019). Residual trace of metal from organometallic catalysts may pose potential toxicity problems that limit their applications in biomedicine (Nachtergael et al., 2015). In order to overcome this issue, organic/metal-free catalysts with efficiency and selectivity/control have been extensively studied in the last decade (Lin et al., 2019; McGraw and Chen, 2020; Hong, 2021). The development of metal-free Lewis pair catalyst systems are considered an effective way. Li's team has developed a series of Lewis pair systems that display good catalytic ability and selectivity (Ji et al., 2018a,b; Ji et al., 2019; Wang et al., 2020). Li et al. successfully copolymerized phthalate with propylene/ethylene oxide at room temperature using a two-part catalyst containing phosphazene base and triethyl borane (TEB) to produce block copolymers with strict AB-type sequence structure and controlled molecular weights (Li et al., 2019a). Zhang et al. synthesized alternating copolymers with high molecular weights (up to 34 kg·mol⁻¹) with metal-free Lewis pairs [phosphazene base (t-BuP₁) as the base and TEB as the acid; Zhang et al., 2020a]. Furthermore, no metal substance being introduced during the polymerization process could be an advantage to expand its application in biomedicine.

One of the limitations of ROCOP is that some functional groups are incompatible during the polymerization process, such as hydroxyl, primary or secondary amines, carboxylic acid, or other protonic functional groups, which could function as chain transfer agents, thereby affecting the molecular weight and distribution of the polymer. Besides, the coexistence of species with different degrees of functionality usually leads to broad or even multimodal molecular weight distributions, which also jeopardizes the chain-end fidelity. Moreover, excessive protonic functional groups may cause catalyst deactivation (Yi et al., 2019). Therefore, post-polymerization modification is an important means to realize multi-functionalities on ROCOP polymers, and the desired functional groups can be accurately connected to the polymer chain by different modification methods (Ntoukam et al., 2020). In addition, the functionalization of the polymer can be achieved without protecting and deprotecting processes for functional monomers. For instance, Sanford et al. incorporated both aldehyde and alkene functionalities into the polymer to achieve orthogonal post-polymerization modification in a one-pot process (Sanford et al., 2018).

Regarding the advantages of dinuclear complexes and metal-free Lewis pairs for making polymers with potential applications in biomedicine, this review focuses on the recent development of ROCOP of epoxides/CO₂ or cyclic anhydrides (Figure 1) to produce polycarbonates, polyesters, or copolymers, with novel homo- and heterodinuclear metal catalysts and metal-free Lewis pair catalyst systems. Furthermore, the post-polymerization functionalization of polycarbonates or polyesters will be summarized, and the influence that multifunctionalities of polymer exert over potential biomedical applications will be emphasized (Scheme 1).

Functional groups such as hydroxyl groups or alkenes on polymer chains can be used as target sites for post-polymerization modification, which can further expand the application potentials of polymers (Farmer et al., 2018). Although the combination of epoxides and CO₂/anhydrides can afford polycarbonates or polyesters by ROCOP, most of the obtained polycarbonates or polyesters lack functionality, restricting their high value-adding applications (Yang et al., 2018). In order to expand the application range of ROCOP polyesters and polycarbonates, epoxides, and anhydrides with different functional groups are of great value. Typical post-polymerization reactions are usually carried out by covalent modifications of the polymer end groups, main chain, and side groups (Gauthier et al., 2009). Among them, thiol-ene click chemistry is the most widely used method (Geschwind et al., 2013; Ntoukam et al., 2020). Besides, the formation of block copolymers or graft copolymers, bearing distinctive block properties (Ghosh et al., 2020; Gregory et al., 2020), could also be a facile approach toward functional materials, such as self-assembled nanomaterials. This section provides an overview of post-polymerization modification for functionalized polycarbonates and polyesters obtained by ROCOP in recent years.

Yi et al. synthesized highly alternating and orthonormal AB-type copolyesters with functional groups of terminal and internal alkenes using different alkene-containing epoxides [VCHO, vinyl PO (VPO), or allyl glycidyl ether (AGE)] and anhydrides [MA, tetrahydrophthalic anhydride (THPA), or tricyclic anhydride (TCA)], and SalcyCrCl/PPNCl as catalyst systems (Figure 11). The author first synthesized polyesters by ROCOP; after that, primary hydroxyl groups were introduced to the polyester chain via the selective hydroboration–oxidation reaction of the terminal alkenes. Then the internal alkenes were quantitatively converted into carboxylic acids, amines, alkyl, and oligo-groups groups by thiol-ene reactions. These copolymers with both hydrophobic and hydrophilic blocks can be self-assembled into nanostructures in aqueous solution, which is expected to be used as antimicrobial agents and biodegradable drug delivery vehicles (Yi et al., 2019).

Sanford et al. used vanillin glycidyl ether (VGE) to directly introduce aldehyde functional group into the polymer chain by copolymerizing with PO and carbic anhydride (CPMA), using the [(^Fsalph)Al(THF)][OTf]/[PPN]₂[ADC] as a bifunctional catalytic system. Then, the poly(VGE-alt-CPMA) was treated by orthogonal post-polymerization modification (Figure 12). The aldehyde was reacted with an amine to form an imine linkage, which could be interesting in biomedical applications due to its pH sensitivity, while the alkene remained unreacted. Analogously, when the alkene was consumed completely through a thiol-ene reaction, the aldehyde remained intact. One step further, under the same reaction conditions, imine functionalization and thiol-ene reaction were combined into one system, achieving orthogonal and dual post-polymerization modification on aliphatic polyester in one pot (Sanford et al., 2018).

Chang et al. introduced tertiary amine functionalities into poly(PA-alt-VCHO) via the thiol-ene reaction. The wettability property of the obtained polymer showed that the introduction of tertiary amine groups in the polymer chain greatly improved the hydrophilicity of polymer nanofibers, leading to potential biomedical applications (Chang et al., 2018).

In 2014, Darensbourg and coworkers synthesized poly(cyclohexadiene carbonate) by ROCOP of CO₂ with 1,2-epoxy-4-cyclohexene, and then they functionalized it by the thiol-ene reaction to afford amphiphilic polymer materials. Thereafter, the polymer was deprotonated with NH₄OH aqueous solution to afford water-soluble polymers (Darensbourg et al., 2014). Shortly after, they also designed another amphiphilic block copolymer using the (salen)CoTFA/PPNTFA catalyst system. The hydrophobic block PPC was synthesized by the ROCOP of PO and CO₂, and the PAGEC block was prepared by the ROCOP of AGE and CO₂. The PAGEC block was then post-functionalized via the thiol-ene reaction to introduce carboxylic acids on the side chain, leading to the formation of amphiphilic triblock polycarbonates. The PAGEC-b-PPC-b-PAGEC can self-assemble into spherical nanoparticles (NPs) with a core-shell morphology in aqueous solution (Wang et al., 2015).

Besides thiol-ene chemistry, Diels–Alder reaction is another facile approach toward post-polymerization modification (Tasdelen, 2011). Hilf et al. prepared a polycarbonate, poly[(furfuryl glycidyl ether)-co-(glycidyl methyl ether)carbonate] poly[(FGE-co-GME)C], using furfuryl glycidyl ether (FGE), glycidyl methyl ether (GME) and CO₂ as monomers, and (R, R)-(salen)-CoCl/PPNCl as the catalyst system (Hilf et al., 2015). The obtained polymer was then reacted with different maleimide derivatives [maleimide, N-(methoxycarbonyl) maleimide, and 1-(3,4-dihydroxyphenyl)-1H-pyrrol-2,5-dione(dopamine maleimide)] through Diels–Alder reaction to achieve reversible functionality.

Different from polyesters or polycarbonates prepared by ROP, ROCOP polycarbonates, or polyesters could potentially be more attractive for biomedical applications. As by simply changing the combination of epoxides and anhydrides, the material properties can be easily tuned. However, despite the significant progress made in catalytic systems, the biomedical potentials of the ROCOP polyesters and polycarbonates have not been well-studied, which is most likely due to the fact that ROCOP conditions are usually not compatible with certain functional groups, such as protic groups, and may induce inactivation/denaturation of the incorporated biomolecules (Feng et al., 2012; Dai and Zhang, 2019). Moreover, the organometallic residuals could be cytotoxic, and the degradation behavior of polymers prepared by ROCOP still lacks proper investigation (Xu et al., 2020). In this section, a few pioneering studies of ROCOP polymers for potential biomedical applications will be outlined.

Integrating bio-imaging and drug delivery into one system makes it possible to combine diagnosis and treatment for diseases such as cancer (Wang et al., 2018). Li et al. developed a reliable and effective tumor imaging platform with ROCOP polycarbonates (Li et al., 2017b). The triblock polycarbonates, poly(allyl glycidyl ether carbonate)-b-poly(propylene carbonate)-b-poly(allyl glycidyl ether carbonate) (PAGEC-b-PPC-b-PAGEC), was prepared by sequential epoxide addition during the ROCOP. The obtained triblock polycarbonates were then modified by the thiol-ene reaction between the allyl groups on the PAGEC block and Boc-protected cysteine. Amphiphilicity was achieved after the deprotection of Boc. The amphiphilic triblock polycarbonates were labeled with gadolinium (Gd³⁺) and self-assembled into polymeric micelles, which showed relatively low cytotoxicity both in vitro and in vivo. The polymer micelles were degradable via the hydrolysis of carbonate bonds to release DPTA/Gd complexes. The tumor MRI showed that these Gd-loaded polymer micelles have excellent MR imaging ability. This study demonstrated that CO₂-based amphiphilic polycarbonates with improved hydrophilicity and functionality can be used as an efficient platform for tumor imaging (Li et al., 2017b).

Doxorubicin (DOX) and curcumin (CUR) have an anti-tumor activity; some studies have shown that CUR expresses its chemo-sensitization action by increasing its accumulation in cancer cells to enhance the anti-tumor ability of DOX. Based on this, Gupta et al. prepared different drug-loaded NPs, consisting of poly(tBGE-alt-PA) with DOX and CUR, and the poly(tBGE-alt-PA) was synthesized with tert-butyl glycidyl ether (tBGE) and PA using the TEB/PPNCl catalyst system (Figure 13). Although poly(tBGE-alt-PA) is biodegradable, TGA results suggested that NPs can be stored for a long time at room temperature. Drug release experiments showed that the in vitro drug release of the NPs followed anomalous transport pattern, with higher cellular drug uptake of DOX and CUR in the NP formulation, compared with free drug. Moreover, drug-loaded NPs had no significant cytotoxicity against MCF-10A cells, and the dual-drug system also showed higher anticancer therapeutic efficacy (Gupta et al., 2019). Kummari et al. tested a few metal-free Lewis pairs on the alternating copolymerization of norbornene anhydride and different epoxides. The obtained polyesters showed good biocompatibility upon human embryonic kidney cells (HEK-293) (Kummari et al., 2019).

Zhu et al. demonstrated the significance of polymer degradation products, besides being used simply as delivery vehicles, in metabolic activities to modulate cell behavior. They used PCL as the macroinitiator to initiate the ROCOP of succinic anhydride (SA) and 2-[(2-(2-(2-meth-oxyethoxy)ethoxy)ethoxy)methyl]oxirane (ME₃MO), leading to the formation of amphiphilic PCL-b-PE block copolyesters (Figure 14). These polymers formed vesicle-like nanostructures via self-assembly. The self-assembled nanostructure was able to be degraded rapidly by lipase to afford metabolites including succinic acid, 6-hydroxyhexanoic acid, and a derivative of glycerol containing tri(ethylene glycol) substituent. These degradation products were found to stimulate the proliferation of dermal fibroblasts, which could be of great value for cell-specific wound healing. This finding signals the importance of designing drug delivery systems with specific metabolic activities (Zhu et al., 2019).

Inspired by the self-healing ability of living organisms, synthetic biomedical self-healing materials have also been extensively studied. Self-healing materials can automatically repair damage to return their original shape, structure, functionality, and physical and chemical properties without external intervention (Chen et al., 2017; Shi et al., 2019). At the molecular level, self-healing methods can be divided into physical events and chemical events (for instance, covalent bonding, free radicals, and supramolecular dynamic bonds; Wang and Urban, 2020). At present, in order to make self-healing materials with good mechanical properties and self-healing ability at the same time, the commonly used method is to prepare multi-block copolymers, in which the hard block provides strength and rigidity for the material and the multivalent supermolecular interactions ensure self-healing (Chen and Guan, 2014; Lee et al., 2020). Darensbourg and Wu's group synthesized a series of CO₂-based polycarbonate elastomers with self-healing ability via a one-pot method, combining ROCOP with the thiol-ene reaction as the post-polymerization modification strategy. Triblock copolymer, PAGEC-b-PPC-b-PAGEC, was prepared first ROCOP. Then, excess CO₂ was removed after the consumption of AGE, followed by the addition of 2-amido ethanethiol to perform thiol-ene modification (Figure 15A), introducing self-healing ability (Yang et al., 2018). Due to the reversible hydrogen bonding effect, the obtained polycarbonates showed good self-healing ability and can almost completely recover without any external stimulation at room temperature. Besides, almost no loss of the mechanical properties and self-healing ability were observed even after repetitive thermoforming (Yang et al., 2018). Another healable CO₂-based thermoplastic elastomer, PCHC-b-PACC-b-PCHC, was synthesized via the addition of N1,N6-dimethyl-N1,N6-bis(2-(4-methyl-1,3,2-dioxaborolan-2-yl)benzyl)-hexane-1,6-diamine (DABE) as a dynamic cross-linker (Figure 15B). Monothioglycerol was added to perform the thiol-ene click reaction. The experimental results showed that before modification, the block polymer had only one T_g (~20°C), but after modification, two T_g values (~−20 and ~100°C) appeared, suggesting the formation of microphase separation and increased hydrophilicity of PACC blocks. The PCHC block offers rigidity, while the dynamic exchange of boronic ester bond ester between the diol groups and telechelic diboronic esters in the soft PACC block/DABE phase contributes self-healing (Yang and Wu, 2019).

Compared with other controlled polymerization reactions, ROCOP provides a more facile method to tailor the material properties of polyesters and polycarbonates by simply changing the monomer combinations of epoxides, CO₂, and cyclic anhydrides. The catalysis of ROCOP has been investigated for decades, and a few comprehensive reviews have been reported. However, the recent development in multi-nuclear organometallic catalytic systems and metal-free catalytic systems has rarely been summarized. Multi-nuclear organometallic catalysts, especially the heteronuclear ones, generally exhibited higher polymerization rates and polymer selectivities than those of the mononuclear analogs, while the metal-free catalytic system is of great potential to be used for the synthesis of biopolymers. Nevertheless, there are still a few main issues to be addressed, including the lack of understanding of elementary steps during the ROCOP, rigorous polymerization conditions (e.g., high CO₂ pressure and high reaction temperature), the lack of stereoselective catalytic systems, and the less well-controlled monomer/block sequence.

In terms of the material properties, though protonic functional groups may not be tolerated during the ROCOP, there are great potentials to introduce functionalities via the post-polymerization modification. The most commonly used approaches are the thiol-ene reaction, hydroboration–oxidation reaction, and Diels–Alder reaction. Most importantly, owing to the alternating monomer sequence in ROCOP polymers, orthogonal functionality is easily accessible to reach versatile properties. Such versatility would be a great advantage for biomedical applications, where no single property fits all needs. However, compared with the vast advances in catalysis study, the potential bioapplications of ROCOP polymer have not attracted enough attention. This leaves many opportunities for the future development of ROCOP polymers tailored for biomedicine, including the accurate control of degradation rate to accommodate different application scenarios, understanding the metabolic activity of degradation products, and introducing versatile functionalities with minimum induced toxicity.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.