Alexander N. Tavtorkin

To reduce the time of postoperative recovery and to prevent post-surgical complications, biocompatible synthetic materials with osteoconductive and osteoinductive properties are used as bone substitutes in large bone defect management. A simplified biomimetic approach to similar materials is based on the use of an inorganic filler, a polymer matrix, and a compatibilizer, mimicking the composition of the natural bone. Based on plate-like micro-sized carbonated hydroxyapatite (pCAp), we prepared compression-molded samples optionally containing an additional polyester component (poly(ε-caprolactone) PCL, poly(L-lactide) PLLA, or poly(L-methylglycolide) PLMG); syntheticblock copolymers comprising fragments of the corresponding polyester and poly(ethylene phosphoric acid) (PEPA) were also prepared and studied asa ‘two-in-one’ polymer matrix/compatibilizer. Bone regeneration experiments involving a three-month rat tibial defect model were conducted with 250–500 μm granules of the composites. Comparative studies of the introduction of the polyester-b-PEPA copolymer into composites revealed a positive effect, which manifests itself in accelerated bone regeneration, which further intensified for pCAp/PEPA-b-PLMG. The latter composite formulation was used to study the results of the introduction of cerium into the filler. One-month experiments with pCAp, CePO₄-doped pCAp, and composites of these inorganic fillers with PEPA-b-PLMG were conducted. For the first time, a positive synergistic effect of the presence of cerium and PEPA in the composite, which appeared in substitution of the implant material by two-thirds of newly formed partly matured bone, was observed four weeks after surgery.

The polymerization of isobutylene allows us to obtain a wide spectrum of polyisobutylenes (PIBs) which differ in their molecular weight characteristics and the chemical structure of chain-end groups. The bulk of the PIBs manufactured worldwide are highly reactive polyisobutylenes (HRPIBs) with –C(Me)=CH₂ end-groups and low-molecular weights (M_n < 5 kDa). HRPIBs are feedstocks that are in high demand in the manufacturing of additives for fuels and oils, adhesives, detergents, and other fine chemicals. In addition, HRPIBs and CMe₂Cl-terminated PIBs are intensively studied with the aim of finding biomedical applications and for the purpose of developing new materials. Both chain control (molecular weight and dispersity) and chemoselectivity (formation of exo-olefinic or –CMe₂Cl groups) should be achieved during polymerization. This review highlights the fundamental issues in the mechanisms of isobutylene polymerization and PIB analysis, examines actual catalytic approaches to PIBs, and describes recent studies on the functionalization and applications of HRPIBs and halogen-terminated PIBs.

Composites of synthetic bone mineral substitutes (BMS) and biodegradable polyesters are of particular interest for bone surgery and orthopedics. Manufacturing of composite scaffolds commonly uses mixing of the BMS with polymer melts. Melt processing requires a high homogeneity of the mixing, and is complicated by BMS-promoted thermal degradation of polymers. In our work, poly(L-lactide) (PLLA) and poly(ε-caprolactone) (PCL) composites reinforced by commercial β-tricalcium phosphate (βTCP) or synthesized carbonated hydroxyapatite with hexagonal and plate-like crystallite shapes (hCAp and pCAp, respectively) were fabricated using injection molding. pCAp-based composites showed advanced mechanical and thermal characteristics, and the best set of mechanical characteristics was observed for the PLLA-based composite containing 25 wt% of pCAp. To achieve compatibility of polyesters and pCAp, reactive block copolymers of PLLA or PCL with poly(tert-butyl ethylene phosphate) (C1 and C2, respectively) were introduced to the composite. The formation of a polyester-b-poly(ethylene phosphoric acid) (PEPA) compatibilizer during composite preparation, followed by chemical binding of PEPA with pCAp, have been proved experimentally. The presence of 5 wt% of the compatibilizer provided deeper homogenization of the composite, resulting in a marked increase in strength and moduli as well as a more pronounced nucleation effect during isothermal crystallization. The use of C1 increased the thermal stability of the PLLA-based composite, containing 25 wt% of pCAp. In view of positive impacts of polyester-b-PEPA on composite homogeneity, mechanical characteristics, and thermal stability, polyester-b-PEPA will find application in the further development of composite materials for bone surgery and orthopedics.

Low-temperature ceramics based on magnesium calcium phosphate cement are a promising resorbable material for bone tissue restoration with the possibility of functionalization. The replacement of the magnesium Mg²⁺ ion with a calcium Ca²⁺ ion at the stage of preparation of the precursor leads to the production of multiphase ceramics containing phases of brushite, monetite, and newberyite, with different dissolution rates. Multiphase ceramics leads to volumetric resorption with preservation of their geometric shape, which was confirmed by the results of an evaluation of the output of magnesium Mg²⁺ and calcium Ca²⁺ ions into the contact solution of the ceramics and the X-ray density of ceramic samples during subcutaneous implantation. The combined introduction of sodium pyrophosphate decahydrate and citric acid monohydrate as setting inhibitors neutralizes their insignificant negative effect on the physico-chemical properties of ceramics (strength, pH, porosity), determining the optimal composition. In vivo experiments with setting inhibitors in the composition of ceramics showed a different biological response, affecting the rate of resorption on par with magnesium ions. Preliminary data on biocompatibility and solubility determined magnesium-calcium phosphate ceramics containing additives that regulate setting to be a potential material for bone tissue restoration and a vector for further research, including in orthotopic implantation models.

Composite biocompatible scaffolds, obtained using the electrospinning (ES) technique, are highly promising for biomedical application thanks to their high surface area, porosity, adjustable fiber diameter, and permeability. However, the combination of synthetic biodegradable (such as poly(ε-caprolactone) PCL) and natural (such as gelatin Gt) polymers is complicated by the problem of low compatibility of the components. Previously, this problem was solved by PCL grafting and/or Gt cross-linking after ES molding. In the present study, composite fibrous scaffolds consisting of PCL and Gt were fabricated by the electrospinning (ES) method using non-functionalized PCL1 or NHS-functionalized PCL2 and hexafluoroisopropanol as a solvent. To provide covalent binding between PCL2 and Gt macromolecules, NHS-functionalized methyl glutarate was synthesized and studied in model reactions with components of spinning solution. It was found that selective formation of amide bonds, which provide complete covalent bonding of Gt in PCL/Gt composite, requires the presence of weak acid. With the use of the optimized ES method, fibrous mats with different PCL/Gt ratios were prepared. The sample morphology (SEM), hydrolytic resistance (FT-IR), cell adhesion and viability (MTT assay), cell penetration (fluorescent microscopy), and mechanical characteristics of the samples were studied. PCL2-based films with a Gt content of 20 wt% have demonstrated the best set of properties.

Ultra-high molecular weight poly-α-olefins are widely used as drag reducing agents (DRAs) for pipeline transportation of oil and refined petroleum products. The synthesis of polyolefin DRAs is based on low-temperature Ziegler–Natta (ZN) polymerization of higher α-olefins. 1-Hexene based DRAs, the most effective at room temperature, typically lose DR activity at low temperatures. The use of 1-hexene copolymers with C8–C12 linear α-olefins appears to offer a solution to the problem of low-temperature drag reducing. The present work aims to develop two-stage synthesis of polyolefin DRAs that is based on selective oligomerization of ethylene in the presence of efficient chromium/aminodiphosphine catalysts (Cr-PNP), followed by polymerization of the olefin mixtures, formed at oligomerization stage, using efficient titanium–magnesium ZN catalyst. We have shown that oligomerization of ethylene in α-olefin reaction media proceeds faster than in saturated hydrocarbons, providing the formation of 1-hexene, 1-octene, and branched C10 and C12 olefins; the composition and the ratio of the reaction products depended on the nature of PNP ligand. Oligomerizates were used in ZN polymerization ‘as is’, without additional treatment. Due to branched character of C10+ hydrocarbons, formed during oligomerization of ethylene, resulting polyolefins demonstrate higher low-temperature DR efficiency at low polymer concentrations (~1 ppm) in comparison with benchmark polymers prepared from the mixtures of linear α-olefins and from pure 1-hexene. We assume that faster solubility and more efficient solvation of the polyolefins, prepared using ‘tandem’ ethylene-based process, represent an advantage of these type polymers over conventional poly(1-hexene) and linear α-olefin-based polymers when used as ‘winter’ DRAs.

In bone surgery and orthopedics, bioresorbable materials can be helpful in bone repair and countering post-op infections. Explicit antibacterial activity, osteoinductive and osteoconductive effects are essential to achieving this objective. Nonwoven electrospun (ES) fibers are receiving the close attention of physicians as promising materials for wound dressing and tissue engineering; potentially, in high contrast with dense materials, ES mats hamper regeneration of the bone extracellular matrix to a lesser extent. The use of the compositions of inherently biodegradable polyesters (poly(ε-caprolactone) PCL, poly(lactoglycolide), etc.), calcium phosphates and antibiotics is highly prospective, but the task of forming ES fibers from such compositions is complicated by the incompatibility of the main organic and inorganic ingredients, polyesters and calcium phosphates. In the present research we report the synthesis of hydroxyapatite (HAp) nanoparticles with uniform morphology, and demonstrate high efficiency of the block copolymer of PCL and poly(ethylene phosphoric acid) (PEPA) as an efficient compatibilizer for PCL/HAp mixtures that are able to form ES fibers with improved mechanical characteristics. The materials obtained in the presence of vancomycin exhibited incremental drug release against Staphylococcus aureus (St. aureus).

Aliphatic polyesters are an important class of polymeric materials for biomedical applications due to their versatile and tunable chemistry, biocompatibility and biodegradability. A capability of direct bonding with biomedically significant molecules, provided by the presence of the reactive end functional groups (FGs), is highly desirable for prospective polymers. Among FGs, N-hydroxysuccinimidyl activated ester group (NHS) and maleimide fragment (MI) provide efficient covalent bonding with –NH– and –SH containing compounds. In our study, we found that NHS- and MI-derived acyl chlorides efficiently terminate living ring-opening polymerization of ε-caprolactone, L-lactide, ethyl ethylene phosphonate and ethyl ethylene phosphate, catalyzed by 2,6-di-tert-butyl-4-methylphenoxy magnesium complex, with a formation of NHS- and MI-functionalized polymers at a high yields. Reactivity of these polymers towards amine- and thiol-containing model substrates in organic and aqueous media was also studied.

Despite the world’s combined efforts, human immunodeficiency virus (HIV), the causative agent of AIDS, remains one of the world’s most serious public health challenges. High genetic variability of HIV complicates the development of anti-HIV vaccine, and there is an actual clinical need for increasing the efficiency of anti-HIV drugs in terms of targeted delivery and controlled release. Tenofovir (TFV), a nucleotide-analog reverse transcriptase inhibitor, has gained wide acceptance as a drug for pre-exposure prophylaxis or treatment of HIV infection. In our study, we explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) (mPEG-b-PEPA) as candidates for developing a long-acting/controlled-release formulation of TFV. Two types of mPEG-b-PEPA with numbers of ethylene phosphoric acid (EPA) fragments of 13 and 49 were synthesized by catalytic ring-opening polymerization, and used for preparing four types of adducts with TFD. Antiviral activity of [mPEG-b-PEPA]TFD or tenofovir disoproxil fumarate (TDF) was evaluated using the model of experimental HIV infection in vitro (MT-4/HIV-1_IIIB). Judging by the values of the selectivity index (SI), TFD exhibited an up to 14-fold higher anti-HIV activity in the form of mPEG-b-PEPA adducts, thus demonstrating significant promise for further development of long-acting/controlled-release injectable TFV formulations.

The control of surface bioadhesive properties of the subcutaneous implants is essential for the development of biosensors and controlled drug release devices. Poly(alkyl ethylene phosphate)-based (co)polymers are structurally versatile, biocompatible and biodegradable, and may be regarded as an alternative to poly(ethylene glycol) (PEG) copolymers in the creation of antiadhesive materials. The present work reports the synthesis of block copolymers of ε-caprolactone (εCL) and 2-ethoxy-1,3,2-dioxaphospholane-2-oxide (ethyl ethylene phosphate, EtOEP) with different content of EtOEP fragments, preparation of polymer films, and the results of the study of the impact of EtOEP/εCL ratio on the hydrophilicity (contact angle of wetting), hydrolytic stability, cytotoxicity, protein and cell adhesion, and cell proliferation using umbilical cord multipotent stem cells. It was found that the increase of EtOEP/εCL ratio results in increase of hydrophilicity of the polymer films with lowering of the protein and cell adhesion. MTT cytotoxicity test showed no significant deviations in toxicity of poly(εCL) and poly(εCL)-b-poly(EtOEP)-based films. The influence of the length of poly(EtOEP)chain in block-copolymers on fibrotic reactions was analyzed using subcutaneous implantation experiments (Wistar line rats), the increase of the width of the fibrous capsule correlated with higher EtOEP/εCL ratio. However, the copolymer-based film with highest content of polyphosphate had been subjected to faster degradation with a formation of developed contact surface of poly(εCL). The rate of the degradation of polyphosphate in vivo was significantly higher than the rate of the degradation of polyphosphate in vitro, which only confirms an objective value of in vivo experiments in the development of polymer materials for biomedical applications.