Promoting vascularization for tissue engineering constructs: current strategies focusing on HIF-regulating scaffolds

ABSTRACT

Introduction: Vascularization remains one of the greatest yet unmet challenges in tissue engineering. When engineered tissues are scaled up to therapeutically relevant dimensions, their demand of oxygen and nutrients can no longer be met by diffusion. Thus, there is a need for perfusable vascular structures. Hypoxia-inducible factors (HIF) act as transcriptional oxygen sensors and regulate a multitude of genes involved in adaptive processes to hypoxia, including angiogenesis. Thus, targeting HIFs is a promising strategy to induce vascularization of engineered tissues.

Areas covered: Here we review current vascularization strategies and summarize the present knowledge regarding activation of HIF signaling by ions, iron chelating agents, α-Ketoglutarate (αKG) analogues, and the lipid-lowering drug simvastatin to induce angiogenesis. Specifically, we focus on the incorporation of HIF-activating agents into biomaterials and scaffolds for controlled release.

Expert opinion: Vascularization of tissue constructs through activation of upstream regulators of angiogenesis offers advantages but also suffers from drawbacks. HIFs can induce a complete angiogenic program; however, this program appears to be too slow to vascularize larger constructs before cell death occurs. It is therefore crucial that HIF-activation is combined with cell protective strategies and prevascularization techniques to obtain fully vascularized, vital tissues of therapeutically relevant dimensions.

Trial registration: ClinicalTrials.gov identifier: NCT03137966.

KEYWORDS:

• Hypoxia-inducible factors
• tissue engineering
• vascularization
• biomaterials
• biofabrication
• ions
• iron chelators

Article highlights

• Vascularization remains a major challenge for tissue engineering.

• Growth factors can induce angiogenesis but only replicate parts of the native signaling cascade, causing immature vessels.

• HIF-activating agents incorporated into biomaterials have successfully been used to induce angiogenesis.

• The native angiogenic program might be too slow to counteract tissue death in thick tissues.

• Combinatorial approaches are necessary to produce viable, vascularized tissues of therapeutically relevant dimensions.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – Projektnummer 326998133 – TRR 225 (subproject C01 to FB Engel) and an individual grant (EN453/11-1 to FB Engel).