Citrate chemistry and biology for biomaterials design

Abstract

Leveraging the multifunctional nature of citrate in chemistry and inspired by its important role in biological tissues, a class of highly versatile and functional citrate-based materials (CBBs) has been developed via facile and cost-effective polycondensation. CBBs exhibiting tunable mechanical properties and degradation rates, together with excellent biocompatibility and processability, have been successfully applied in vitro and in vivo for applications ranging from soft to hard tissue regeneration, as well as for nanomedicine designs. We summarize in the review, chemistry considerations for CBBs design to tune polymer properties and to introduce functionality with a focus on the most recent advances, biological functions of citrate in native tissues with the new notion of degradation products as cell modulator highlighted, and the applications of CBBs in wound healing, nanomedicine, orthopedic, cardiovascular, nerve and bladder tissue engineering. Given the expansive evidence for citrate's potential in biology and biomaterial science outlined in this review, it is expected that citrate based materials will continue to play an important role in regenerative engineering.

Role of Citrate in Pathophysiology and Medical Management of Bone Diseases

“…In light of its structural role, citrate has been used to explain the changes in the bone microarchitecture typical of some diseases [47]. In addition, a series of citrate-based materials for orthopaedic applications have been developed to favour the osteoinductive and osteoconductive properties of scaffolds for bone tissue engineering [48,49], as well as to promote bone healing in other surgical procedures [50,51,52].…”

Degradation properties of a biodegradable shape memory elastomer, poly(glycerol dodecanoate), for soft tissue repair

“…When injected in vivo, hydrogels have been prone to migration and biodegradable polymers like PLGA, PLA and PCL predominantly undergo bulk degradation causing rapid changes in mechanical integrity during the degradation timeframe [5]. Biodegradable elastomers like polyglycerol sebacate(PGS) and poly-diol citrates have been increasingly studied for soft tissue repair applications [6][7][8][9]. These materials are synthesized from components of common metabolic pathways and consequently break down into biologically compatible byproducts.…”

Biomaterial‐Based Metabolic Regulation in Regenerative Engineering

“…[15,84,85] Meanwhile, citrate serves as a multifunctional and cytocompatible [86] monomer, which contributes to the development of a family of versatile and functional CBBs with tunable mechanical and biodegradable properties. [87,88] It turned out that citrate released from CBBs during degradation entered hMSCs via plasma membrane transporter solute carrier familiar 13, member 5 (SLC13a5) to modulate two main energy producing pathways by elevating OXPHOS while inhibiting glycolysis, which ultimately resulted in significantly elevated intracellular ATP levels (Figure 5Aii). [80] Given metabolic reprogramming from glycolysis to OXPHOS is required for Adv.…”

“…Intracellular citrate is well‐known as an intermediate metabolite, playing an important role in regulating energy homeostasis, since it not only modulates the activity of key enzymes in both catabolic and anabolic pathways, but also could convert to acetyl–CoA, the direct substrate for fatty acid biosynthesis and histone acetylation . Meanwhile, citrate serves as a multifunctional and cytocompatible monomer, which contributes to the development of a family of versatile and functional CBBs with tunable mechanical and biodegradable properties . It turned out that citrate released from CBBs during degradation entered hMSCs via plasma membrane transporter solute carrier familiar 13, member 5 (SLC13a5) to modulate two main energy producing pathways by elevating OXPHOS while inhibiting glycolysis, which ultimately resulted in significantly elevated intracellular ATP levels (Figure Aii) .…”

“…For example, citric acid with three carboxylic acid (–COOH) groups has shown potent ion‐chelating capabilities. Therefore, poly(octamethylene citrate) (POC) and water soluble poly(polyethylene glycol citrate‐ co ‐ N ‐isopropylacrylamide) (PPCN), belong to the citrate‐based biomaterials (CBBs) family, employ citric acid as the major antioxidative, multifunctional monomer and thereby are capable of chelating ions, scavenging free radicals, and inhibiting lipid peroxidation. Further incorporation of ascorbic acid into the POC network resulted in the development of a new polymer named poly(octamethylene citrate ascorbate) (POCA),where the ascorbate incorporation synergized with citric acid by increasing the accessibility of the carboxyl and hydroxyl groups on citric acid leading to increased metal chelation onto POC ( Figure A).…”