Common plastic wastes will be fragmented into microplastics over time, which cannot be biologically assimilated, thus causing persistent pollution and damage to humans and animals. By contrast, bacterial polyhydroxyalkanoates (PHA), a class of diverse and natural intracellular biopolyesters accumulated as carbon and energy storage materials, have been shown to be biodegradable and biocompatible. Thus, PHA are increasingly attractive as eco-friendly biodegradable plastics for replacing petrochemical plastics. 

The advantages of PHA include excellent and controllable biodegradability, inherent biocompatibility, diverse mechanical properties and thermo-processability^[2,3]. Benefiting from these features, PHA can be developed for medical microspheres, medical slow-release carriers, human implantation materials, antibacterial fibers and feeds.

Several studies have provided evidence that PHA is suitable as implanted scaffolds for bone tissue engineering to promote cellular osteogenesis. A study entitled "Enhanced bone regeneration via PHA scaffolds coated with polydopamine-captured BMP2" combined the advanced 3D printing technique with a simple functionalized process to create functionalized 3D-printed PHA scaffolds as a versatile platform for bone tissue regeneration. The P34HB-related biodegradable product 3-hydroxybutyrate(3HB) exhibited an inherent osteoinductive property, which may help P34HB scaffolds to promote bone regeneration to some extent^[4,5].

In another study, PHA was used to prepare highly open porous microspheres(OPMs) of 300–360 µm in diameter, combining the advantages of microspheres and scaffolds to serve as injectable carriers harboring proliferating stem cells^[6]. In addition to the convenient injection to a defected tissue, PHA OPMs protect cells against stresses during injection, allowing more living cells to proliferate and migrate to damaged tissues.

The studies above showed the advantage of PHA's biocompatibility and function of tissue regeneration. While other studies focus on d-β-hydroxybutyrate (d-3HB), which is a monomer of microbial poly-d-β-hydroxybutyrate (PHB). It is also a natural ketone body produced during carbohydrate deprivation to provide energy to the body cells, heart, and brain. 

Fig. 2. Medical use of 3-hydrocybutyric acid (3HB) ^[7].

In recent years, increasing evidence demonstrates that d-3HB can induce pleiotropic effects on the human body, which are highly beneficial for improving physical and metabolic health. The benefits of endogenous d-3HB include improving performance in ultra-endurance events^[8] , enhancing body composition^[9], reducing levels of bad LDL cholesterol^[10], altering metabolism-related hormones^[11], suppressing appetite^[12] and maintaining intestinal health status^[13].

Specifically, lifestyle alteration is a key strategy used to tackle obesity and long-term KDs (ketogenic diet) or very low-energy diets have already been explored as a promising treatment strategy. d-3HB was shown to be able to improve the blood lipid profile in obese adults by a reduction in low density lipoprotein (LDL) cholesterol, increase in high density lipoprotein (HDL) cholesterol, smaller adipocyte cell volume, and inhibition of lipolysis via a G-protein-coupled receptor (GPCR) which reduced subsequent release of serum lipolytic products^[14]. At the cellular level, d-3HB markedly increased mitochondrial uncoupling in brown adipose tissue (BAT) which increased mitochondrial respiration and thermogenesis, thereby resulting in increased resting energy expenditure (REE) in the obese^[15,16].

A number of studies have investigated the pathways by which d-3HB acts to ameliorate Alzheimer’s and Parkinson’s Disease in rodent models^[17,18]. In fact, in one clinical report of a patient with sporadic ALZ following treatment with KME, the patient demonstrated remarkable improvements in mood, self-caring ability, cognitive, and physical performance^[19].

d-3HB also shows importance in protecting animals against a variety of bacterial diseases for growth. Clear evidence indicating that PHB conferred protection to Artemia host against V. campbellii by a mechanism of inducing heat shock protein (Hsp) 70^[20]. PHB also has been studied as a feed additive for large yellow croakers and weaned piglets. As fish feed additive for growing large yellow croakers, PHB could increase fish weights 10-25%^[21].

Fig. 3. PHB as safe food additive ^[22].

In recent years, the use of exogenous ketone supplements, which induce rapid ketosis without the need to adhere to the KD, has increased in popularity. Ingestion of d-3HB could effectively optimize the body composition of athletes, leading to enhanced exercise performance. However, ingestion of ketone salts and esters was associated with unwanted GI side effects or requires further degradation before releasing d-3HB for absorption. To our knowledge, there has been no direct investigation based on supplementing the free acid form of d-3HB as a beverage drink to humans or animals yet due to difficulties in obtaining the free acid form in large amounts.

To date, the majority of patented methods related to the production of exogenous d-3HB were through chemical synthesis ^[23]. While recently, PHB could be efficiently produced through bacterial synthesis using a new strain of bacteria known as Halomonas TD01^[24]. Hence, the recently patented technology which utilizes a biosynthetic process to produce d-3HB acid on a kilogram scale is considered a first-time success within this field.

In conclusion, PHA and d-3HB have great potential in medical application with their inherent biocompatibility. We hope that the availability of PHA and d-3HB acid on a large scale may attract and aid scientists and researchers worldwide in developing novel treatments which will benefit the overall metabolic health of humans and potentially extend human life expectancy.

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