Biosynthetic strategies of medical polyhydroxyalkanoate （PHA） and their new developments for human health

doi:10.12211/2096-8280.2025-059

Synthetic Biology Journal

Biosynthetic strategies of medical polyhydroxyalkanoate （PHA） and their new developments for human health

TIAN Yingru¹, HUANG Xiaoyun¹, DAO Jinwei², LI Yuehao¹, XU Tao¹, YANG Hui¹, WAN Dandan¹, WEI Daixu³

^1.Qujing University of Medicine & Health Sciences，Qujing 655100，Yunnan，China
^2.Dehong Biomedical Engineering Research Center，Dehong Normal University，Dehong 678400，Yunnan，China
^3.Chengdu University，Clinical Medical College and Affiliated Hospital，Chengdu 610106，Sichuan，China

Received:2025-06-12 Revised:2025-11-04 Published:2025-11-10
Contact: DAO Jinwei, WEI Daixu

医用聚羟基脂肪酸酯（PHA）的生物合成策略及其在人类健康领域的新进展

田英入¹, 黄晓云¹, 刀金威², 李玥昊¹, 徐涛¹, 杨辉¹, 万丹丹¹, 魏岱旭³

^1.曲靖健康医学院，云南曲靖 655100
^2.德宏师范学院德宏生物医药工程研究中心，云南芒市 678400
^3.成都大学临床医学院与附属医院，四川成都 610106

通讯作者: 刀金威,魏岱旭
作者简介:田英入（1996—），女，硕士研究生。曲靖健康医学院临床学院教师。研究方向为生物材料、合成生物学、组织工程与再生医学、生殖医学、妇产科学、生理学。 E-mail：tianyinrude@163.com
黄晓云（1982—），曲靖健康医学院临床医学院副教授。主要研究小细胞肺癌（NSCLC）的发病机制、治疗药物和智能给药系统等多个领域，目标是识别疾病中的关键分子和通路机制，以开发可行的治疗目标和方法用于临床应用。E-mail:953614419@qq.com
刀金威（1986—），男，博士，德宏师范学院副教授。研究方向为生物材料学、医学组织工程学和病原生物学。 E-mail：daojw15@tsinghua.org.cn
魏岱旭（1986—），男，博士，成都大学临床医学院及附属医院教授、博士生导师、硕士生导师。主要从事聚羟基脂肪酸酯（PHA）及其酮体衍生物（3HB）的生物学效应及综合利用，涉及合成生物学、组织工程与再生医学、医用微纳米器件、智能递药系统、医学美容及化妆品、益生菌外泌体、可降解微塑料毒理、脑科学与抗衰老等领域，曾带领本科生获得2019年和2021年iGEM金奖。 E-mail：weidaixu@cdu.edu.cn
第一联系人：共同第一作者
基金资助:
四川省卫生健康委员会医学科学研究项目(24WSXT106);中国陕西省自然科学基础研究计划项目(2024JC-YBMS-706);自贡医学大数据与人工智能协同创新项目(2023-YGY-1-02);自贡市重点科技计划项目(2022ZCNKY07);自贡市重点科技计划项目(2024-NKY01-01);云南省科学技术厅-云南中医药大学基础研究联合基金(202101AZ070001-102);云南省教育厅科学研究基金项目(2023J1773);云南省科技厅科技计划项目(202401AZ070001-097);曲靖健康医学院校级科学研究基金项目(2025ZD04)

Abstract

Abstract:

Polyhydroxyalkanoates (PHA) constitute a versatile class of microbial polyesters that exhibit exceptional biocompatibility, tunable biodegradability, and a broad spectrum of mechanical and chemical properties. These characteristics render PHA highly suitable for diverse biomedical applications, including tissue engineering scaffolds, targeted drug delivery systems, wound dressings, and implantable devices. Notably, the degradation products of PHA—such as 3-hydroxybutyrate—are endogenous metabolites, thereby minimizing immunogenic responses and enhancing long-term biocompatibility compared to conventional synthetic polymers. Recent advances in synthetic biology have significantly enhanced PHA biosynthesis. Metabolic engineering strategies—such as CRISPR/Cas9-mediated genome editing for redirecting carbon flux toward PHA accumulation, CRISPR interference (CRISPRi) for modulating competing pathways, and optimization of promoter and ribosome-binding site (RBS) libraries—have enabled precise control over monomer composition and polymer properties. Additionally, microbial morphological engineering, including FtsZ-targeted cell elongation, has been employed to increase intracellular PHA content to over 90% of cellular dry weight. These developments have facilitated the synthesis of tailored PHA variants, ranging from rigid poly(3-hydroxybutyrate) (PHB) to elastomeric poly(3-hydroxybutyrate-co-4-hydroxybutyrate) (P34HB). Medical-grade PHA has demonstrated significant translational potential across multiple therapeutic domains. Injectable porous microspheres composed of poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBVHHx) have been developed for minimally invasive bone regeneration. Electrospun P34HB scaffolds exhibit concurrent antibacterial and pro-angiogenic activities, accelerating wound healing. PHA-based nanocarriers enable sustained drug release in the context of Alzheimer's disease and systemic lupus erythematosus. Furthermore, virus-mimetic PHA particles have been exploited as adjuvant systems to enhance antigen presentation in tuberculosis and COVID-19 vaccine platforms. Future perspectives emphasize the convergence of synthetic biology, materials science, and clinical translation to fully realize the biomedical potential of PHA. Next-generation industrial biotechnology (NGIB), utilizing halophilic microorganisms for continuous fermentation under open conditions, coupled with advanced downstream purification protocols, is anticipated to enhance the scalability and accessibility of medical-grade PHA. Integration with emerging technologies such as 3D bioprinting and organoid culture systems is expected to expand PHA's utility in complex, patient-specific tissue engineering applications. Collectively, these advances position PHA as a promising platform biomaterial for next-generation regenerative medicine and targeted therapeutic strategies.

Key words: Polyhydroxyalkanoate (PHA), Synthetic biology, Biomedical materials, Tissue engineering, Biocompatibility, Degradability

摘要：

聚羟基脂肪酸酯（PHA）是一类具有生物相容性、生物可降解性以及优良材料学性能的生物合成聚酯，在医药领域展现出巨大的应用潜力。然而，产能低限制了PHA的应用。近年来，合成生物学技术的发展为PHA的优化生产提供了新途径。本文综述了PHA作为医用材料的优势，包括单体多样性、可控降解性及优异的生物相容性；探讨了合成生物学技术在PHA生产中的应用，如CRISPR/Cas工具、启动子工程、RBS优化、微生物细胞形态工程、染色体整合技术等策略，这些策略可优化合成途径和提高产量，并且推动工业化制备医用级PHA的进展。我们进一步阐述了医用级PHA近些年在骨修复、皮肤再生、心血管工程等领域取得的显著应用成果。未来，融合多学科创新有望突破PHA的技术壁垒，使其成为生物医用材料领域的核心选项，推动再生医学的发展。

关键词: 聚羟基脂肪酸酯（PHA）, 合成生物学, 生物医用材料, 组织工程, 生物相容性, 可降解性

CLC Number:

TQ323.4

TIAN Yingru, HUANG Xiaoyun, DAO Jinwei, LI Yuehao, XU Tao, YANG Hui, WAN Dandan, WEI Daixu. Biosynthetic strategies of medical polyhydroxyalkanoate （PHA） and their new developments for human health[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2025-059.

田英入, 黄晓云, 刀金威, 李玥昊, 徐涛, 杨辉, 万丹丹, 魏岱旭. 医用聚羟基脂肪酸酯（PHA）的生物合成策略及其在人类健康领域的新进展[J]. 合成生物学, DOI: 10.12211/2096-8280.2025-059.

Figures/Tables 3

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PHA	Tg (℃)	T_m (℃)	Rm (MPa)	Ym (MPa)	Eb (%)	Xc (%)	WCA (℃)	Ta (℃)
Commercialized
PHB	-1.20-4.0	162.0-179.0	18.5-43.0	108.0-554.0	4.5-5.0	60.0-80.0	89.0	212.0
P4HB	-51.0 to-48.0	53.0-60.0	50.0	70.0-670.0	1000.0	ND	74.0-80.0	308.5
PHBV	-1.7-5.0	120.0-170.0	2.7	65.8	30.0-123.0	58.1-65.7	69.6-80.8	279.6
PHBHHx	-1.8-4.0	52.0-151.0	4.1	130.4	107.7-270.0	25.0-43.0	85.2-87.2	220.0
P34HB	-4.2-7.4	50.0-166.0	23.1-25.8	902.0	3.7-13.0	80.0-90.3	60.2-96.1	239.6
PHBVHHx	-2.6 to -1.2	69.6-152.1	5.1	284.6	276.9-739.7	ND	90.3-90.6	255.5
Uncommercialized
PHV	-15.0	119.0	31.0	ND	ND	ND	ND	258.0
PHHx	-28.2	ND	ND	ND	ND	ND	ND	211.6
PHP	-20.0	77.0	27.0	300.0	ND	ND	ND	ND
PHO	-35.4	52.8-61.0	6.0-10.0	33.0-41.0	ND	36.7	ND	256.2
PHBHP	-3.1 to -2.1	119.8-162.8	ND	ND	ND	ND	ND	150.0
PHBHV4HB	-51.0 to -10.0	55.0-131.0	12.8-14.3	30.0-140.0	316.0-937.0	ND	ND	ND

PHA	Tg (℃)	T_m (℃)	Rm (MPa)	Ym (MPa)	Eb (%)	Xc (%)	WCA (℃)	Ta (℃)
Commercialized
PHB	-1.20-4.0	162.0-179.0	18.5-43.0	108.0-554.0	4.5-5.0	60.0-80.0	89.0	212.0
P4HB	-51.0 to-48.0	53.0-60.0	50.0	70.0-670.0	1000.0	ND	74.0-80.0	308.5
PHBV	-1.7-5.0	120.0-170.0	2.7	65.8	30.0-123.0	58.1-65.7	69.6-80.8	279.6
PHBHHx	-1.8-4.0	52.0-151.0	4.1	130.4	107.7-270.0	25.0-43.0	85.2-87.2	220.0
P34HB	-4.2-7.4	50.0-166.0	23.1-25.8	902.0	3.7-13.0	80.0-90.3	60.2-96.1	239.6
PHBVHHx	-2.6 to -1.2	69.6-152.1	5.1	284.6	276.9-739.7	ND	90.3-90.6	255.5
Uncommercialized
PHV	-15.0	119.0	31.0	ND	ND	ND	ND	258.0
PHHx	-28.2	ND	ND	ND	ND	ND	ND	211.6
PHP	-20.0	77.0	27.0	300.0	ND	ND	ND	ND
PHO	-35.4	52.8-61.0	6.0-10.0	33.0-41.0	ND	36.7	ND	256.2
PHBHP	-3.1 to -2.1	119.8-162.8	ND	ND	ND	ND	ND	150.0
PHBHV4HB	-51.0 to -10.0	55.0-131.0	12.8-14.3	30.0-140.0	316.0-937.0	ND	ND	ND

Technology Category	Tools/Strategies	Application Case	Effects/Advantages
CRISPR/Cas Tools	CRISPR/Cas9	prpC gene deletion in Halomonas bluephagenesis	16-fold increase in 3HV proportion in PHBV^[19]
	CRISPR/Cas9	Deletion of byproduct genes (pflB etc.) in E. coli	Enhanced cell growth and PHA yield^[20]
	CRISPRi	Suppression of propionate consumption pathway	Improved substrate to PHB conversion efficiency^[21]
	CRISPRi	Inhibition of 4HB competing pathways	Controlled 3HB/4HB monomer ratio^[22]
Promoter Engineering	Inducible promoter	Activation of PHA biosynthesis genes in Pseudomonas putida	Significantly improved PHA synthesis efficiency^[23]
	Constitutive promoter	phaC continuous expression in Yarrowia lipolytica	Promoted fatty acid copolymer synthesis^[24]
	Dual promoter	The dual promoters (T7 and Pporin) act in concert on the phaCAB operon in Halomonas elongata.	27.5% increase in PHB production^[25-26]
	Promoter library	High-efficiency promoter screening for 4HB transferase gene	Achieved 80wt% P34HB accumulation^[27]
RBS Optimization	RBS library design (computational tools + OLMA)	Optimization of PHA synthase gene translation in Cupriavidus necator	PHB production increased from 0% to 92% of cell dry weight^[28-30]
RBS Optimization	RBS library optimization	PHB production enhancement in E. coli	Yield improvement from 0% to 92% of cell dry weight^[28-31]
Pathway Fine-tuning	Dynamic range control system	Regulation of 4HB synthesis genes in H. bluephagenesis	P34HB production >36 g/L in 7 L culture (16 mol% 4HB content) ^[32]
	Protein autoactivation system (PhaR/PhaP1)	Single/dual-copy autoactivation system in H. bluephagenesis	Achieved 97.4 g/L cell density (76.3% PHA of dry weight)^[33]
	Temperature sensitive bioswitch	PHA monomer ratio control in E. coli	Produced diblock/random copolymers with tunable structures^[34]
	Toxin-antitoxin stabilization (hbpB/hbpC)	H. bluephagenesis continuous subculture	Maintained stability for 7 days without antibiotics^[35]
	Multi-inducible system (10 signals)	Coordinated regulation of chromoproteins, lycopene and PHB in H. bluephagenesis	Enhanced cell proliferation and product yield^[36]
Metabolic Engineering	Gene knockout (FadA/FadB/GabD)	Attenuation of β-oxidation cycle, prevention of SSA loss	Significantly increased PHA accumulation^[37]
Metabolic Engineering	Cofactor optimization (Udh overexpression)	Enhanced NADH/NADPH supply	Improved PHA synthesis efficiency^[37-38]
Morphological Engineering	Division ring disruption (FtsZ-GFP)	Cell elongation in Halomonas campaniensis LS21	PHB content increased from 56wt% to 78wt%^[39]
	Cytoskeleton regulation (mreB knockout + conditional complementation)	Cell rounding/volume increase in Halomonas campaniensis LS21	Achieved 5 μm cell diameter with significantly improved PHB production^[40-41]
	Multidivision induction (ΔminCD + ftsQ/Z/mreB overexpression)	Synergistic multidivision and elongation in E. coli JM109	PHB accumulation increased by >80%^[42-43]
Chromosomal Integration & Membrane Engineering	Chromosomal integration	udhA gene integration in Halomonas TD08 (NADPH-dependent transhydrogenase)	PHB increased from 87% to 92% CDW, glucose conversion efficiency from 30% to 42% ^[44]
Chromosomal Integration & Membrane Engineering	OM-deficient strains	Low-endotoxin strains (e.g., ClearColi™ BL21(DE3)) for PHA production	Reduced endotoxin content, simplified purification, improved biocompatibility ^[45-46]

Technology Category	Tools/Strategies	Application Case	Effects/Advantages
CRISPR/Cas Tools	CRISPR/Cas9	prpC gene deletion in Halomonas bluephagenesis	16-fold increase in 3HV proportion in PHBV^[19]
	CRISPR/Cas9	Deletion of byproduct genes (pflB etc.) in E. coli	Enhanced cell growth and PHA yield^[20]
	CRISPRi	Suppression of propionate consumption pathway	Improved substrate to PHB conversion efficiency^[21]
	CRISPRi	Inhibition of 4HB competing pathways	Controlled 3HB/4HB monomer ratio^[22]
Promoter Engineering	Inducible promoter	Activation of PHA biosynthesis genes in Pseudomonas putida	Significantly improved PHA synthesis efficiency^[23]
	Constitutive promoter	phaC continuous expression in Yarrowia lipolytica	Promoted fatty acid copolymer synthesis^[24]
	Dual promoter	The dual promoters (T7 and Pporin) act in concert on the phaCAB operon in Halomonas elongata.	27.5% increase in PHB production^[25-26]
	Promoter library	High-efficiency promoter screening for 4HB transferase gene	Achieved 80wt% P34HB accumulation^[27]
RBS Optimization	RBS library design (computational tools + OLMA)	Optimization of PHA synthase gene translation in Cupriavidus necator	PHB production increased from 0% to 92% of cell dry weight^[28-30]
RBS Optimization	RBS library optimization	PHB production enhancement in E. coli	Yield improvement from 0% to 92% of cell dry weight^[28-31]
Pathway Fine-tuning	Dynamic range control system	Regulation of 4HB synthesis genes in H. bluephagenesis	P34HB production >36 g/L in 7 L culture (16 mol% 4HB content) ^[32]
	Protein autoactivation system (PhaR/PhaP1)	Single/dual-copy autoactivation system in H. bluephagenesis	Achieved 97.4 g/L cell density (76.3% PHA of dry weight)^[33]
	Temperature sensitive bioswitch	PHA monomer ratio control in E. coli	Produced diblock/random copolymers with tunable structures^[34]
	Toxin-antitoxin stabilization (hbpB/hbpC)	H. bluephagenesis continuous subculture	Maintained stability for 7 days without antibiotics^[35]
	Multi-inducible system (10 signals)	Coordinated regulation of chromoproteins, lycopene and PHB in H. bluephagenesis	Enhanced cell proliferation and product yield^[36]
Metabolic Engineering	Gene knockout (FadA/FadB/GabD)	Attenuation of β-oxidation cycle, prevention of SSA loss	Significantly increased PHA accumulation^[37]
Metabolic Engineering	Cofactor optimization (Udh overexpression)	Enhanced NADH/NADPH supply	Improved PHA synthesis efficiency^[37-38]
Morphological Engineering	Division ring disruption (FtsZ-GFP)	Cell elongation in Halomonas campaniensis LS21	PHB content increased from 56wt% to 78wt%^[39]
	Cytoskeleton regulation (mreB knockout + conditional complementation)	Cell rounding/volume increase in Halomonas campaniensis LS21	Achieved 5 μm cell diameter with significantly improved PHB production^[40-41]
	Multidivision induction (ΔminCD + ftsQ/Z/mreB overexpression)	Synergistic multidivision and elongation in E. coli JM109	PHB accumulation increased by >80%^[42-43]
Chromosomal Integration & Membrane Engineering	Chromosomal integration	udhA gene integration in Halomonas TD08 (NADPH-dependent transhydrogenase)	PHB increased from 87% to 92% CDW, glucose conversion efficiency from 30% to 42% ^[44]
Chromosomal Integration & Membrane Engineering	OM-deficient strains	Low-endotoxin strains (e.g., ClearColi™ BL21(DE3)) for PHA production	Reduced endotoxin content, simplified purification, improved biocompatibility ^[45-46]

Application	PHA Type	Key Findings/ Innovations	References
Bone Tissue Repair & Aerospace	PHBVHHx	- PHBVHHx OPM enable minimally invasive injection and bone regeneration.support bone health in microgravity.	[18]
	P4HB	- P4HB-OPM promotes bone regeneration without cells/growth factors.	[57]
	P34HB	- PHA nanoparticles (P34HB, PHBVHx) loaded with BMPs	[12,58-59]
Skin Tissue Repair & Medical Cosmetology	PHB, PHBV	- PHB/PHBV has the properties of promoting skin repair, loading drugs or cells, and mimicking the extracellular matrix.	[60]
	P34HB	- Electrospun P34HB scaffolds accelerate wound healing with antibacterial/angiogenic properties.	[61]
	PHBVHHx	- PHBVHHx nanoparticles enhance microneedle delivery of hair-growth drugs (e.g., ritlecitinib) for androgenetic alopecia.	[62]
Cardiovascular Tissue Engineering	PHBHHx	- PHBHHx patches for vascular grafts.	[63]
	P34HB	- P34HB coatings for coronary stents.	[64]
	PHBV	- PHBV/PCL electrospun scaffolds with VEGF improve vascular patency and regeneration.	[65]
	PHB	- The composite material of PHB and ePTFE is suitable for cardiovascular sensing.	[66]
Oral Soft Tissue Repair	P34HB	- P34HB/ZnO scaffolds with antibacterial properties promote gum regeneration.	[67]
Oral Soft Tissue Repair	PHBV	- P(HB-50HV) supports high proliferation of gingival fibroblasts.	[68]
Adjuvant Immune Regulation	PHBVHHx	- AZA-loaded PHBVHHx nanoparticles reduce toxicity and enhance efficacy in treating lupus.	[69]
Vaccines & Virus Mimetics	PHA-based particles	- PHA particles simulate viral structures to enhance antigen presentation (e.g., for TB/COVID-19).	[14]
Vaccines & Virus Mimetics	PHA-based particles	-Challenges include endotoxin contamination from E. coli.	[70]
Treatment of Alzheimer’s Disease	PHBVHHx	- PHBVHHx microspheres enable sustained release of huperzine A, reducing neurotoxicity.	[71]
Organoid Assistance	PHBVHHx	- Porous PHBVHHx microspheres support 3D cell growth and mimic extracellular matrix.	[72-74]

Biosynthetic strategies of medical polyhydroxyalkanoate （PHA） and their new developments for human health

医用聚羟基脂肪酸酯（PHA）的生物合成策略及其在人类健康领域的新进展

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