Surgical Bioengineering of the Microvasculature and Challenges in Clinical Translation

Abstract

Tissue and organ dysfunction are major causes of worldwide morbidity and mortality with all medical specialties being impacted. Tissue engineering is an interdisciplinary field relying on the combination of scaffolds, cells, and biologically active molecules to restore form and function. However, clinical translation is still largely hampered by limitations in vascularization. Consequently, a thorough understanding of the microvasculature is warranted. This review provides an overview of (1) angiogenesis, including sprouting angiogenesis, intussusceptive angiogenesis, vascular remodeling, vascular co-option, and inosculation; (2) strategies for vascularized engineered tissue fabrication such as scaffold modulation, prevascularization, growth factor utilization, and cell-based approaches; (3) guided microvascular development via scaffold modulation with electromechanical cues, 3D bioprinting, and electrospinning; (4) surgical approaches to bridge the micro- and macrovasculatures in order to hasten perfusion; and (5) building specific vasculature in the context of tissue repair and organ transplantation, including skin, adipose, bone, liver, kidney, and lung. Our goal is to provide the reader with a translational overview that spans developmental biology, tissue engineering, and clinical surgery.

Impact Statement

This translational article provides a concise review of microvascular engineering efforts to date within the context of grafts, flaps, and entire organ replacement. Our article systematically and logically discusses current developments, challenges, and novel approaches in microvascular engineering. It provides a readable starting point for understanding various approaches and the implications of successful vascularization at the microvascular level as well as how surgical approaches can be used to facilitate connections to the recipient macrovasculature.

Keywords

bioengineering surgery flap graft transplant microvasculature

Introduction

Tissue and organ dysfunction are major causes of morbidity and mortality, impacting all medical specialties. For example, soft tissue loss that occurs following oncologic extirpation is broadly comparable with that affected by ischemic or infectious etiologies. In all scenarios, clinicians seek to restore function, form, or both, thereby preserving both quality and quantity of life. Unfortunately, this is not always achievable despite clinical advances. Reconstructive and transplant surgeons are tasked with replacing tissue and organs, respectively. Regrettably, replacement grafts, flaps, and organs are scarce and complication prone.

Grafts are pieces of tissue transferred to a remote anatomical site without intrinsic blood supply (Fig. 1A).¹ Skin grafts (SG) have become ubiquitous to treat small tissue defects, irrespective of etiology.^2–9 Because SGs rely on diffusion from the recipient site for initial oxygen delivery, they need to be quite thin to limit necrosis. Thus, they are typically only suitable for the reconstruction of <2 mm thick defects.¹⁰ Complete vascularization from the recipient takes several weeks.^11,12 If the recipient site is suboptimal, as seen following irradiation, the graft may never vascularize.¹³

FIG. 1.

Diagram showing differences between graft, flap, and whole organ replacement. (A) Superficial skin injury repaired with a skin graft with no vascular pedicle. (B) Complex soft tissue injury repaired with a flap containing its own blood supply via a vascular pedicle. (C) Diseased kidney removal followed by transplantation of a healthy kidney with vascular pedicle anastamosis. Diagrams created using BioRender.com.

In contrast, flap surgery is defined by the transfer of vascularized tissue (e.g., adipose, bone) with its feeding artery and draining vein (vascular pedicle [VP]) (Fig. 1B). Since flaps carry their own blood supply, they can be any thickness and are suitable for wound reconstruction of any depth. This autologous tissue transplantation has revolutionized reconstructive options across different anatomical sites.^14–18 However, complications are common,¹⁹ including flap loss secondary to thrombosis (up to 10%),^20–22 and donor site morbidity with scarring, dehiscence, weakness, and paresthesia.^23,24 Patients may have inadequate donor sites that preclude flap surgery.^25,26

For entire organ replacement, the principles of vascular anastomosis allow for allogenic exchange (Fig. 1C). Notwithstanding donor scarcity, organ transplantation has specific challenges including immunosuppression and rejection risk. Despite a two-fold increase in transplants over the past 30 years, the number of waiting patients has increased six-fold.²⁷

The goal of tissue engineering (TE) is to create replacement tissues and organs. This interdisciplinary field relies on scaffolds, cells, and biological molecules to restore both form and function. Despite significant advances, clinical translation is limited largely by insufficient vascularization and slow perfusion upon implantation. This critical bottleneck limits implementation and the surgeon’s dream of being able to pull replacement parts “off the shelf.” Unfortunately, the ability to engineer a perfusable hierarchical microcirculation still precludes us. Here, we provide a microvascular overview and current surgical bioengineering attempts for graft, flap, and organ vascularization (Table 1).

Table 1.

The Native Microvascular Anatomy, Specialized Function, Regulation Mechanisms, and Cellular Markers for (A) Skin, (B) adipose Tissue, (C) Bone, (D) Liver, (E) Kidney, and (F) Lung

Organ	Native microvasculature	Specialized function	Regulation	Marker examples
(A) Skin	• Two parallel plexuses with capillary loops extending perpendicularly between them^28,29	• Temperature regulation via the autonomic nervous system³⁰ • Synthesize and secrete chemokines and cytokines, recruit immune cells in response to dysfunctions³¹	• Sympathetic activation causing release of norepinephrine, neuropeptide-Y, adenosine triphosphate (ATP)²⁸ • Protein kinase C (PKC)-alpha isoform regulates endothelial cell function and microvascular homeostasis³²	• Neural cell adhesion molecule (NCAM)³³
(B) Adipose	• Microvessels adjacent to each adipocyte³⁴	• Paracrine adipocyte-endothelial cell communication³⁵ • Free fatty acid processing³⁶ • Regulates expandability of tissue during overfeeding and obesity³⁷	• Vasoactive factors releasing Angiotensin (Ang) II³⁸ • Argonaut regulates vascularization and metabolic activity of adipose tissue³⁵ • Leptin induction of endothelin-1 leads to increased adipocyte size and vasculature³⁹	• Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1)⁴⁰ • Snail family transcriptional repressor I (SNAI1)³⁶ • CD10 • CD200⁴¹ • Adiponectin⁴²
(C) Bone	• Nutrient artery enters cortex, sprouts repeatedly until arterial sprouts extend longitudinally and radially within Haversian system⁴³	• Participates in all stages of bone healing process⁴⁴ • Facilitates interaction between endothelial cells and osteoblasts³¹	• Runx2 regulates mesenchymal stromal cells to osteoblast differentiation process to promote neovascularization^40,45 • VEGF, Ang1, sonic hedgehog (SHH), fibroblast growth factor 2 (FGF2), platelet-derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), bone morphogenetic protein 2 (BMP2), all regulate angiogenesis and endothelial bone communication in wound healing⁴³	• Endothelial nitric oxide synthase (eNOS) • FMS-like tyrosine kinase (FLT) • Matrix metalloproteinase (MMP) 3⁴⁶ • Brain microvascular endothelial cell 1 (BMEC)-1⁴⁷
(D) Liver	• Dual blood supply with terminal hepatic venules and several portal venules at periphery, with hepatic sinusoids between them forming a hexagonal structure⁴⁸	• Fenestrated endothelial cells that have endocytic functions and phagocytic Kupffer cells important for host defense⁴⁹ • Perfuse sinusoids to facilitate transvascular exchange between the blood and liver cells⁴⁸	• Terminal portal venule at transitional part of sinusoid releases ET-1 to cause contraction of sinusoidal endothelial fenestra via ET-B receptors to increase sinusoidal and presinusoidal microvascular resistance⁵⁰	• Pianp (Leda-1) • Liver sinusoidal endothelial cell 1 (LSEC)⁵¹
(E) Kidney	• Glomerular and peritubular capillary beds that supply cellular constituents of the kidney⁵²	• Local modulation of renal blood flow and intraglomerular function • Vasa recta establish counter current mechanisms to concentrate urine⁵³	• Purinoceptors (P1/P2) widely expressed in renal microvascular and tubules regulate renal blood flow and glomerular filtration rate⁵⁴	• Parietal epithelial cells (PEC) 1⁵⁵ • P2X⁵⁶
(F) Lung	• Bronchial circulation, systemic vascular supply to lung that progressively branches, and the pulmonary circulation, which forms a closed circuit between the heart and lungs⁵⁷	• Gas exchange at the pulmonary capillary bed level⁵⁸ • Neutrophil margination⁵⁹	• Hypoxia activation of epidermal growth factor receptor (EGFR) tyrosine kinase (TK) leads to arginase expression and proliferation of hPMVEC to induce angiogenesis⁶⁰ • circGSAP can mitigate pulmonary vascular remodeling⁶¹ • miR-375-3p regulates pulmonary endothelial cell function⁶²	• SRY-related HMB-box (Sox) 17⁶³ • Lectin Helix pomatia^64,65

The Microvasculature

The microvasculature is crucial to end-organ functionality. Native microvasculatures are characterized by organized tree-like branching of arterioles into progressively smaller vessels down to capillaries, converging into postcapillary venules. This permits blood flow regulation via arterioles, oxygen diffusion via capillaries, and immune cell modulation via venules.^28–32 Thus, the potential of hierarchical microvascular replacement far exceeds just tissue reconstruction. The development of a rapidly perfused and tailored microvasculature would profoundly impact our ability to generate replacement tissue and treat microvascular dysfunction across all anatomical sites^33–36 and redefine surgical treatments.³⁷ To develop the best engineering and surgical practices for microvascular creation, an understanding of native microvascular development is necessary.

Spouting angiogenesis

Sprouting angiogenesis (SA) (Table 2A), activated under ischemic conditions, releases proangiogenic factors like vascular endothelial growth factor (VEGF) to promote new vessel formation.³⁹ This process involves the tip cell, which migrates toward VEGF, and the stalk cell, which proliferates to extend the vessel (Fig. 2A).^40,41 VEGF-Notch signaling impacts cellular regulation; Delta-like ligand 4 (DLL4)-Notch interaction influences endothelial cells (EC) fate toward stalk cells, and Notch signaling suppression enhances tip cell filopodia activity.^42,43 VEGF gradients govern tip and stalk cell activities, causing sprout extension and luminal formation.^45–49 The process is completed when EC migration stops and adherens junctions are established.⁶⁶

FIG. 2.

(A) Steps of angiogenesis, including the VEGF interaction causing stalk cell elongation and ultimate lumen formation. (B) Intussusceptive angiogenesis, including capillary wall invagination followed by endothelial cell reorganization leading to invasion of pericytes and fibroblasts to form a pillar. (C) Vascular remodeling, with endothelial advancement leading to lumen collapse on poorly perfused lumen and endothelial arrangement and formation of two lumens in well-perfused lumen. (D) Vascular co-option, with tumor cells migrating along existing vessels to ultimately cause tumor proliferation and vessel regression. (E) Inosculation, with the application of skin graft and formation of vessels between underside of graft and wound bed capillary to form a blood supply. Created using BioRender.com. VEGF, vascular endothelial growth factor.

Table 2.

Detailing Specifics of (A) Sprouting Angiogenesis, (B) Intussusceptive Angiogenesis, (C) Vascular Remodeling, (D) Vascular Co-Option, and (E) Inosculation

	Triggers	Primary cell types involved	Signaling pathway molecules
(A) Sprouting angiogenesis	• Ischemic tissue releases VEGF and other growth factors	• Endothelial cells form capillary sprouts based on VEGF gradient • Pericytes function to modulate the ECM and paracrine signaling to stabilize ECs¹⁰²	• DLL4 • Notch¹⁰³
(B) Intussusceptive angiogenesis	• Vessel maturation and regression response to angiogenic and remodeling factors	• Endothelial cells reorganize during capillary wall invagination to form intraluminal pillar⁷³ • Pericytes and fibroblasts produce extracellular matrix between new lumens¹⁰²	• Thrombospondin 1 • Membrane type 1 (MT1)-MMP • Nitric oxide¹⁰⁴
(C) Vascular remodeling	• Adaptation to tissue needs in response to inflammation, vascular injury and hemodynamics	• Pericytes function to bind EC and cause involution of cell⁸⁰ • Type I pruning: EC rearrangement to collapse lumen • Type II pruning: EC rearrangement to form two separate luminal compartments⁷⁸	• WNT • Notch • Ang/TIE • DLL4/Notch⁷⁹
(D) Vascular co-option	• Malignancy triggering cell-cell interactions	• Cancer cells migrate along abluminal surface of preexisting vessels • Cancer cells infiltrate tissue space along preexisting vessels⁸³	• Ang-2 • MMP-2⁸² • Tie-2¹⁰⁵
(E) Inosculation	• Exposed vessels in proximity typically occurring after a skin graft	• Graft microvasculature regression and replacement by ingrowing microvessels from host tissue^106,107	• VEGF • bFGF¹⁰⁸

EC, Endothelial cell; WNT, Wingless-related integration site.

Pericytes, mesenchymal-origin cells associated with ECs, modulate vascular stability, and angiogenesis.^51,52 Recruited by ECs through factors such as platelet-derived growth factor (PDGF)-B, they contribute to basement membrane (BM) formation and EC stabilization.^54,55 Their density varies by tissue type, reflecting their function in regulating vascular permeability, integrity, and functionality.^56–58 While VEGF remains the most studied angiogenic growth factor (GF), it is impacted by multiple GFs such as hepatocyte GF, which enhances VEGF; keratinocyte GF, which induces angiogenesis and stabilizes endothelial barriers; as well as angiogenic lymphokines (angiokines), which modulate capillary development.^67–69 Multiple GFs, cytokines, lipids, and stimuli impact the regulation of junctional molecules and cell surface receptors.⁷⁰

Intussusceptive angiogenesis

Intussusceptive angiogenesis (IA) (Table 2B) is the process by which new vessels are formed by dividing an existing vessel.⁷¹ During capillary replication and remodeling, the capillary wall invaginates into the vascular lumen to form an intraluminal pillar (Fig. 2B).⁷¹ The interendothelial junctions reorganize, forming a central perforation that is invaded by pericytes and myofibroblasts depositing ECM.⁷² In contrast to SA, where pericytes participate in vessel development, stabilization, maturation, and regression; pericytes in IA help form the pillar interstitial core to allow pillar growth and splitting of the initial capillary.^73,74 During this, the BM remains intact; ECs enlarge and flatten, resulting in a lower metabolic cost.^75,76 IA is primarily regulated by hemodynamic forces but is also influenced by GFs.⁷⁶ However, unlike SA, VEGF is downregulated during IA.⁷⁷ Generally, the microvasculature is initiated through SA with IA playing a subsequent role.⁷¹

Vascular remodeling

Vascular remodeling (Table 2C) involves growth, regression, and change in lumen size in response to tissue demands (Fig. 2C).⁷⁸ Pruning, microvessel regression, is influenced by blood flow, with nonperfused vessels prone to pruning.^78,79 Two pruning types exist: type I occurs without flow and leads to endothelial advancement and lumen collapse, and type II begins in perfused vessels, with EC rearrangement maintaining the lumen before eventual collapse into separate compartments.⁸⁰ Signaling cascades such as Notch, Ang/TIE, and DLL4/Notch, facilitate balance between vessel formation and regression.⁸¹ Pericytes, through interaction with EC C-X-C Motif Chemokine Receptor 3 receptors and activation of calpains, play a role in selective pruning.⁸² Calpains, tightly regulated proteases, are involved in cell processes including proliferation, apoptosis, and differentiation.⁸³

Vascular co-option

Co-option (Table 2D) allows cancer cells to utilize preexisting vessels for tissue expansion independent of angiogenesis (Fig. 2D).^84,85 This interaction complicates traditional therapeutic targets and⁸⁶ tumors grow until these vessels are fully integrated⁸⁷; Ang-2 then leads to endothelial detachment and vessel regression, promoting tumor advancement.^84,88 After regression, both IA and SA occur. While associated with malignancy, similar mechanisms have been observed in wound healing.⁸⁹

Inosculation

Inosculation (Table 2E), critical for split-thickness skin graft (STSG) viability, involves forming a connection between the embedded graft microvasculature and recipient capillaries (Fig. 2E).⁹⁰ Although STSGs are ubiquitously used for skin repair, they are limited by availability, leading to the development of engineered substitutes such as decellularized dermal matrices.^91,92 These matrices also utilize inosculation, but exhibit slower vascularization compared with autologous STSG.⁹³ Revascularization rate is influenced by thickness, with thinner grafts revascularizing faster.⁹⁴ While thicker grafts offer better coverage, diffusion challenges lead to higher failure rates.

These processes are also driven by metabolic demand and hemodynamic cues⁹⁵ that complement GFs, such as blood flow shear forces and extracellular matrix (ECM) stiffness.⁹⁶ Metabolism influences GF activity⁹⁷ with capillary density being directly proportional depending on tissue type.⁹⁸ Organotypic vasculature is the principle that tissue-specific ECs have cellular and molecular heterogeneity⁹⁹ that modulate vascular differentiation and function.¹⁰⁰ Native angiogenic complexity¹⁰¹ warrants multiple approaches to vascularized TE.

Strategies for Vascularized Engineered Tissue

Successful tissue replacement extends beyond simple vascularization, ideally requiring a microvasculature with a topology that supports rapid perfusion and functional demands. The interplay between microvascular and macrovascular systems is crucial for tissue function.^109,110 For engineered tissues to survive, vascular networks are needed and a variety of approaches have been trialed.¹¹¹

Scaffolds

Vascularized tissue regeneration is facilitated by scaffolds.^111,112 A diverse group of biomaterials exists including natural and synthetic. Aiming to mimic ECM, they provide structural support and mechanical stability.^113–115 Additionally, scaffolds must exhibit biocompatibility to reduce immunogenic responses.¹¹⁶ Scaffold modification, through prevascularization, GFs, and cell seeding offers therapeutic and unique advantages for microvascular engineering (Fig. 3).

FIG. 3.

Diagram discussing current in vitro approaches for vascularizing engineered tissue. (A) Unmodified scaffold invaded by SA, degrading the scaffold and leaving behind ECM and vasculature. (B) Prevascularized scaffolds such as one created using wire molding being invaded by SA and inosculating with preexisting channels to allow for growth and subsequent ECM formation. (C) Scaffold being invaded by SA toward a gradient of proangiogenic growth factors. (D) Cell seeding acellular scaffold with cells and growth factors prior to incubation. Created with BioRender.com. ECM, extracellular matrix; SA, sprouting angiogenesis.

Natural scaffolds (Figs. 3A and 4A), commonly collagen derived, are favorable due to biocompatibility and ECM similarity.^139,140 Once implanted, ECs invade and remodel the biomaterial to establish vascularization.^141,142 Collagen scaffolds can also be modified to promote intrinsic vascularization.¹⁴³ One study showed that hFGF incorporated into a collagen sponge was released with sponge biodegradation and exhibited dose-dependent angiogenesis.¹⁴⁴ Similar examples of natural scaffolds include gelatin and hyaluronic acid.^145,146

FIG. 4.

(A) A natural collagen-based scaffold from Szychlinska et al.¹⁵⁶ (B) A synthetic scaffold PCL/PLGA/beta-Tricalcium phosphate scaffold from Sun et al.¹⁵⁷ (C) A hybrid scaffold example GelMA from Leu Alexa et al.¹⁵⁸ Images (A–C) adapted under the terms and conditions of the Creative Commons Attribution (CC BY) license (CC BY 4.0 Deed | Attribution 4.0 International | Creative Commons). GelMA; gelatin methacryloyl; PCL, polycaprolactone; PLGA, poly(lactic-co-glycolic) acid.

Synthetic scaffolds (Fig. 4B), such as poly(lactic-co-glycolic) acid (PLGA), polylactic acid (PLA), polycaprolactone, and polyglycolide, provide mechanical strength but are less favorable due to incompatibility.^147–149 For example, PLA is more resistant to biodegradation, but its acidic byproducts adversely impact cell infiltration and vascularization.¹⁵⁰

Hybrid scaffolds (Fig. 4C), such as gelatin methacryloyl (GelMA), permit increased bioactivity with improved stability.¹⁵¹ In one study, new vessel formation, collagen deposition, and re-epithelization were accelerated by cross-linking GelMA functionalized with endothelin-1 to promote wound healing.¹⁵² These scaffolds have gained attention as they permit effective cell attachment and proliferation.^153,154 A study by our groups showed that scaffolds made from microporous granular GelMA could control microvascular topology.¹⁵⁵

Vascularization adjuncts

Prevascularization (Fig. 3B) involves creating a scaffold microvasculature in vitro prior to implantation. Theoretically, this should expedite perfusion and reduce the metabolic effort needed for complete vascularization.^175,176 Techniques for creating prevascularized tissues include bioprinting, microfluidics, wire molding, and microvascular fragments (MVF).^131,177 While these channels are not a vessel, they mimic vessels but require cellularization prior to effectively conducting blood flow.

Bioprinting (Table 3A) uses advanced manufacturing, such as extrusion and laser-based approaches, to create cell-laden 3D structures mimicking tissue, with microchannels that can be endothelialized for blood vessel simulation.^117,122 This method allows for complex, signal-rich structures but faces challenges including bioink cytotoxicity.^121,123

Table 3.

Detailing Techniques, Materials, Advantages, and Disadvantages of (A) Bioprinting, (B) Microfluidic Technology, (C) Wire Molding, (D) Microvascular Fragments

	Technique	Materials	Advantages	Disadvantages
(A) Bioprinting	• Laser-based • Extrusion-based • Inkjet-based¹¹⁷ • Microextrusion molding • Laser sintering • Stereolithographic¹¹⁸	• Bioink¹¹⁹ • Hydrogel filaments¹¹⁸ • Alginate hydrogels • Gelatin • Fibrin • Collagen • Cryogels¹²⁰	• Allows for deposition of signaling biologics¹²¹ • 3D networks that are perfusable and can be lined with different cell types¹²² • In situ bioprinting possible¹¹⁸	• Can contain cytotoxic compounds detrimental to viability¹²³ • Limited structural complexity due to high water content¹²⁰ • Lack of longitudinal information¹¹⁸
(B) Microfluidic technology	• Passive microfluidics (microfiltration, inertial focusing and secondary flows, pinch flow fractionation) • Active microfluidics (acoustic, electric, magnetic, thermal, pressure filled-driven micromixers)¹²⁴	• PDMS • Hydrophilic cellulose- or nitrocellulose-based substrates¹²⁵ • UV-curable, biocompatible, and transparent resins¹²⁶	• High control over geometrical features to micrometer-sized channels¹²⁷ • Biomimicry of physiochemical conditions of cell environment, biofabrication, distribution, and control of culture media¹²⁷ • Can be combined with bioprinting¹²⁸ • Self-assembly through tubulogenesis¹²⁹	• Often limited to thin tissue, not easily separated for implantation¹³⁰ • Less control of network architecture¹²⁹
(C) Wire molding	• Prepolymer solution distributed around a wire subsequently withdrawn once polymerized^129,131	• GelMA¹³² • Hydrogel precursors¹²⁹	• Evenly distributed microchannels within large tissue constructs¹³¹ • Better able to vascularize 3D constructs • Resultant channels able to function as native vessels following endothelial cell seeding¹³¹	• Difficulty creating an in vivo model
(D) Microvascular fragments	• Functional vessel segments derived from arterioles, capillaries, and veins¹³³ • Adipose tissue through collagenase digestion¹³⁴	• Adipose tissue and associated vasculature¹³⁵	• Increased angiogenesis, improved nutritive tissue perfusion, and suppressed apoptosis¹³⁶ • Easily isolated from adipose tissue • Can be combined with biomaterials easily for tissue regeneration¹³⁴	• Undigested connective tissue within isolates can prevent interconnection of individual MVC into new networks¹³⁷ • Cryopreservation was associated with an increased rate of necrotic cells and reduced number of transplantable MVF¹³⁸

GelMA; gelatin methacryloyl; MWF, microvascular fragments; PDMS, Polydimethylsiloxane.

Microfluidic technology (Table 3B) leverages lithography to construct detailed microfluidic networks, facilitating precise geometrical control and influencing cell growth through fluid manipulation in micrometer-sized channels.^178,179 This method mirrors natural vascular development but is generally confined to producing only thin tissues within the microfluidic setup, complicating implantation.¹³⁰ Given implantation difficulty, this technology remains largely restricted to simple in vitro microvascular testing.^179–181

Wire molding (Table 3C) creates microchannels by molding polymers around suspended wires that are subsequently removed, leaving behind perfusable channels. These channels, once endothelialized, can function like natural vessels.^129,182

Microvascular fragments (Table 3D) are functional vessel segments derived from adipose tissue that rapidly reassemble upon implantation.¹⁸³ Compared with SVF, they have increased levels of ECs and perivascular cells facilitating engraftment and vasculogenic efficiency.¹⁸⁴ MVF have been shown to inosculate with host vessels and accelerate scaffold perfusion,¹³⁴ irrespective of origin and degree of vessel specialization.¹⁸⁵

Growth factors

GFs (Fig. 3C), such as proteins and miRNA, are biologically active molecules that can affect cell growth and vascularization.¹⁸⁶

Proteins

Proteins (Table 4A), such as VEGF, enhance neovascularization through EC migration and vessel sprouting.^187,188 Scaffolds with controlled GF gradients were found to increase vascularization, showing clinical promise.^189–191 However, GF degradation by enzymes poses a challenge.¹⁹² Timing of GF release affects vascular development; simultaneous application of proangiogenic and promaturation factors hinders angiogenesis, whereas sequential application enhances microvessel density.¹⁹³ Thus, temporal control of GF signaling appears crucial for therapeutic vascularization.

Table 4.

Substrate Examples Along with Advantages and Disadvantages for (A) Protein and (B) microRNA

Growth factors examples	Substrate examples:	Advantages:	Disadvantages:
(A) Protein	• PDGF¹⁵⁹ • VEGF • FGF¹⁶⁰ • TGF-beta¹⁶¹	• Well studied, with studies showing enhanced vascularization, osteogenesis, scaffold resorption¹⁶² • Scaffolds can act as a delivery system for GFs¹⁶³ • Potentially tunable action via rational and combinatorial protein engineering techniques¹⁶⁴ • Bioactive factors can be chemically immobilized or encapsulated in polymer matrices to prevent degradation¹⁶⁵	• Spatio-temporal control over location and bioactivity is crucial to achieve therapeutic effect¹⁶⁵ • Typically water-soluble macromolecules with relatively delicate structure¹⁶⁶ • Immunogenicity and short half-life¹⁶⁷
(B) miRNA	• miRNA-17-92 cluster¹⁶⁸ • miRNA-132¹⁶⁹ • miRNA-210¹⁷⁰	• Able to target 3′-untranslated regions of targets to upregulate proangiogenic factors¹⁷¹ • Can be used to assist in differentiation of pluripotent stem cells and mature vascular cells¹⁶⁸ • Both miRNA replacement and induction methods to improve angiogenesis¹⁷²	• Less than optimal delivery systems¹⁶⁸ • Difficulty achieving efficient biodistribution and activity in target tissue to minimize off-target effects¹⁷³ • Plasma levels of miRNA often quickly cleared¹⁷⁴

GF, growth factor; TGF, Transforming growth factor; VEGF, vascular endothelial growth factor.

miRNA

miRNA (Table 4B) plays a regulatory role in angiogenesis, influencing signaling pathways to encourage vascular growth.¹⁹⁴ For example, miRNA-503 overexpression in ECs enhances migration and proliferation by modulating cyclin E.¹⁷² One study demonstrated how miRNAs regulate angiogenesis through NADPH oxidase-dependent mechanisms in ECs.¹⁹⁵

Cell-based approaches

Cell-based approaches, through cell seeding, coculturing, and cell-loaded micropatterning utilize cells to create functional constructs to aid in angiogenesis.

Cell seeding (Fig. 3D, Table 5A) of stem cells or ECs into scaffolds can promote vascularization following implantation.^178,196,197 Scaffold porosity influences cell proliferation; larger pores aid vascularization but reduce mechanical strength.^198–200 Seeding methods include: (1) passive, where cells are simply pipetted onto the scaffold, but unfortunately the yield is low (10–25%)^201,202; (2) dynamic, using rotational or vacuum systems to enhance cell distribution coming at the expense of practicality and cell viability^202–204; and (3) electrostatic, where cell adhesion is encouraged through surface charge but is cumbersome.^{202,205–207}

Table 5.

Detailing Cell-Based Approach Examples, Cell Types, Advantages, and Disadvantages of Cell Seeding (A), Coculturing (B), and Cell-Loaded Micropatterning (C)

	Examples/mechanism	Primary cell type	Advantages	Disadvantages
(A) Cell seeding	Passive seeding^201,326 – Static seeding – Gravitational seeding²⁰²	• Endothelial cells • Smooth muscle cells (SMCs)	• Simple, widely used	• Least efficient cell-seeding method^201,202 • Difficulty achieving uniform level
	Dynamic seeding²⁰² – Rotational seeding²¹⁵ – Vacuum seeding²¹⁶	• Endothelial cells • SMCs • Fibroblasts²¹⁷	• Increased cell seeding efficiency	• Concerns about cell morphology
	• Electrostatic cell seeding	• Endothelial cells • SMCs	• Higher efficiency than dynamic seeding²⁰⁵	• No safety studies looking at long-term effects
	• Magnetic cell seeding	• Endothelial cells • SMCs	• Rapid graft production and reproducible results • Increased cell adhesion mimicking native vessels²⁰²	• Long-term complications need to be assessed prior to clinical use
(B) Coculturing	• Combines cell types crucial to angiogenesis in undifferentiated and differentiated forms	• Endothelial cells • Mesenchymal stem cells (MSCs) • Endothelial progenitor cells (EPCs) • Microvascular and adult endothelial cells²¹⁸	• MSC-ECs and hiPSC-ECs are easily isolated, can be differentiated in vitro, and can act as an autologous cell source²¹⁸	• Immunomodulation of stem cells in coculture needs further assessment in vivo²¹⁹
(C) Cell-loaded micropatterning	Form patterned cells, or spheroids on cell culture substrates via chemical or physical cross-linking²²⁰ – 2D cell patterning – Plasma etching – 3D microorganized cells – Cellular aggregation	• Endothelial cells • Hydrogel scaffolds²¹⁴ • MSCs	• Highly accurate and reproducible cellular array²²¹ • Possible clinical benefit for transplanting cell and polymer combinations in a minimally invasive manner²²⁰	• Long-term complications need to be assessed prior to clinical use

Coculturing (Table 5B) involves combining different cell types in vitro to mimic angiogenesis. Pericytes cocultured with ECs can induce BM development and recruit specific factors for capillary formation.^208–210 Strategies also include preseeding scaffolds with cells and GFs, with some studies engineering cells to coexpress PDGF-BB and VEGF.^211–213

Cell-loaded micropatterned (Table 5C) hydrogels represent an approach where elastomeric microdevices guide cells in building a microvasculature, offering the potential for creating tissue-specific microengineered vasculatures.²¹⁴

Guided Microvascular Development

Tissue vascularization is difficult to replicate in TE.²²² Postimplantation scaffold vascularization often lacks defined architecture, hindering tissue replacement. Creating patterned microvasculatures on scaffolds can support “like tissue with like tissue” replacement, crucial for scaling up TE.²²³ Scaffold modulation with electromechanical cues and techniques like electrospinning and 3D printing help guide cells to replicate native tissues more accurately.^224,225

Electromechanical cues

Electrical and mechanical stimulation plays a significant role in inducing hierarchical microvascular development (Fig. 5A).^226–228 Scaffold modulation can mimic natural electromechanical cues and facilitate vascularization through methods such as cellular alignment, predefined vascular channels, and GF release.^{224,229–231}

FIG. 5.

Guided microvascular development examples. (A) Differences in fluorescence images between micropunctured (MP) and non-MP control group with increased vascularity with MP; microgel size was found to play a role in vascularization as detailed by Ataie et al.¹⁵⁵ (B) A 3D-printed cell-laden mineralized scaffold that demonstrated the stiffness of the scaffold impacting DNA content, ALP activity, and osteogenic differentiation as detailed by Zhang et al.²³⁹ (C) An electrospun ECM-like construct able to be used for TE as detailed by Zulkifli et al.²⁴⁰ Images (A–C) adapted under the terms and conditions of the Creative Commons Attribution (CC BY) license (CC BY 4.0 Deed | Attribution 4.0 International | Creative Commons).

3D printing

3D printing allows for precise cell and biomaterial placement and has found utility in generating vasculatures with defined topology (Fig. 5B).^231–233 Three basic requirements in microvascular bioprinting include: creation of hollow, endothelialized channels; biochemical and biophysical cues to induce endothelial sprouting; and flow-mediated conditioning for maturation.¹⁹¹ Studies have demonstrated 3D-printed scaffolds seeded with stem cells can form new vascular networks that integrate with host tissue.²³⁴

Electrospinning

Electrospinning employs electrostatic forces to generate fibrous scaffolds that aim to mimic native ECM and provide a conducive environment for vascular cell guidance (Fig. 5C).²³⁵ Despite its precision, electrospinning has limitations with mechanical strength and cell density control compared with other techniques.²³⁵ However, advancements have demonstrated its potential in vascular TE, such as electrospun vein grafts.^236,237 Use of electrospinning in conjunction with cell seeding also has been shown to promote vascularization.²³⁸ Unfortunately, with all these modalities, there exists difficulty in bridging the microvasculature to the macrovasculature.

Surgical Approaches to Bridge the Micro- and Macrovasculatures

Ideally, engineered tissue would be anastomosed directly to the recipient vasculature to restore perfusion. However, since this is not yet achievable, current attempts aim to create a proangiogenic environment at the recipient site and/or within the scaffold/graft/flap itself.²⁴¹ Until vascular ingrowth occurs (around 2 weeks), cellular hypoxia can be significant.²⁴² Consequentially, engineered tissues are limited in maximal achievable thickness by oxygen diffusion limitations (∼250 µm).²⁴³ Many approaches and materials have attempted to integrate an anastomosable segment within a vascularized graft itself with varying degrees of success.^244–246 Unfortunately, thrombosis is commonplace in small vessel replacements²⁴⁷ requiring innovative microsurgical approaches to enhance connection between the micro- and macrovasculatures.

Arteriovenous loops

Surgical approaches to induce recipient capillary formation were first shown with arteriovenous loops (AVLs) (Fig. 6A).²⁴⁸ AVLs utilize an expendable vein to connect the macrovascular arterial and venous systems. This deliberate fistula creates a unique microenvironment from which new capillaries can grow. It is believed that mechanical shear stress emanating from the AVL takes precedence in stimulating the neo-microvasculature,^249,250 typically after 14 days.²⁵¹

FIG. 6.

Surgical approaches to bridge the micro- and microvasculature. AVL (A) diagram showing an existing paired artery and vein that is subsequently created into an arteriovenous loop by anastomosing a vein graft directly between the two to induce angiogenesis. An existing vascular pedicle (B) diagram showing angiogenesis occurring toward a scaffold in the presence of underlying existing microvasculature. Micropuncture (C) diagram showing angiogenesis occurring in the locations of the micropuncture causing angiogenesis from both arterial and venous micropunctures. Diagrams (A–C) created using BioRender.com. AVL, arteriovenous loop.

Plastic surgeons have historically used this approach to generate vascularized tissue in challenging clinical scenarios.²⁵² The thrombotic risk of traditional free-flaps using vein conduits was a significant impetus for AVL development.²⁵³ When first used clinically, AVLs were characterized by a temporary end-to-side vein conduit that provided adequately mature vascular flow in preparation for flap transfer.^254,255 Subsequently, the AVL was bisected and the surgeon was able to anastomose the flap outside of an ill-prepared recipient vasculature^257,257 as seen in patients with trauma or atherosclerosis.²⁵⁸ The risk-benefit profile of this approach has been thoroughly evaluated and deemed to be safe.^259,260 Thus, it represents a verified microsurgical approach that can promote the vascularization of implanted biomaterials.

Most recently, AVLs have been explored for TE.^250,261 For example, AVL placed within a polycarbonate chamber filled with fibrin showed enhanced angiogenesis.²⁶² AVLs placed within cross-linked collagen/glycosaminoglycan chambers resulted in a heavily vascularized tissue chamber with the formation of alpha-Smooth muscle actin (SMA)-positive arterioles.²⁶³ This suggests the versatility of AVLs to induce vascularization in diverse biomaterials even within poorly vascularized native recipient tissues.²⁶⁴ The success of AVLs with TE in the research arena has now been clinically translated for large bone defect reconstruction where AVLs were combined with cancellous bone grafts and fibrin scaffolds.²⁶⁵

Unfortunately, some shortcomings exist with AVLs including the prolonged time (up to 12 weeks) required for a new and complete capillary network to develop,^250,264,266 potential unwanted systemic hemodynamic manifestations of this deliberate fistula, and requisite microsurgical expertise to execute them.^266,269,270

Vascular pedicles

Unmodified scaffolds are often difficult to vascularize secondary to limited GF supply (Fig. 6B).²⁷¹ To mitigate this, VPs have been utilized. In this approach, a large surface area of recipient macrovasculature (artery and/or vein) is placed in direct contact with the graft/flap/biomaterial that needs to be vascularized. While eliciting less vascularization than AVLs,²⁷² VP provides a technically simple proangiogenic surgical platform to build upon and is especially useful to those lacking microsurgical expertise.²⁷³ Similar to AVLs, they can also be used alongside other engineered approaches, such as scaffold microchannels²⁷³ and ASC seeding²⁷⁴ with the pedicle facilitating voluminous vascularization²⁷⁵ depending on the exact configuration.

Flow-through or ligated VPs were analyzed for their proangiogeneic potential in a murine model, and it was shown that flow-through VPs were associated with improved patency, angiogenesis, and tissue production.²⁷⁶ Similar results were seen when VP was used to vascularize a collagen-chitosan scaffold to promote vascularized adipose formation.²⁷⁷

Like AVLs, VPs have also been translated into clinical care already in a variety of settings for both simple wound repair²⁷⁸ and more complex reconstructive approaches. 3D-printed biodegradable scaffolds were used in combination with corticoperiosteal flaps (CPF) for critical bone defect regeneration. In this study, a patient with a 36-cm tibial defect underwent intramedullary nail fixation and scaffold implantation, after which a flow-through CPF was placed within the scaffold. VP provided the impetus for scaffold vascularization that resulted in limb-salvage and functional restoration. Subsequently, Scanning electron microscopy confirmed the presence of vascularized bone.²⁷⁹

The advantages of VP included relatively easy surgical execution, no systemic hemodynamic alterations, and verified clinical translation already. However, like AVLs, they suffer from deferred angiogenesis²⁸⁰ and the inability to achieve/restore prompt blood flow to the adjacent implant. This has led to newer microsurgical approaches being developed in an attempt to promote rapid angiogenesis.

Micropuncture

With both AVLs and VPs there exists an angiogenic delay, likely because of time-limited BM breakdown of the vessel wall that is necessary prior to EC sprouting and new luminal formation (Fig. 6C). We recently hypothesized that this enzymatic degradation process could be mechanically expedited by puncturing the targeted macrovasculature. In micropuncture (MP), we use 30–100 μm diameter needles to generate precise microperforations in the recipient vascular segment just prior to collagen scaffold implantation. These MP “mother” vessels permit immediate cellular extravasation and microvascular outgrowth without themselves suffering thrombosis or significant hemorrhage.²⁸¹ When combined with modified scaffolds, microvascular development can be further controlled through this unique surgical bioengineering approach.¹⁵⁵

The MP technique has not been applied clinically as we just recently described the approach. However, the potential limitations include bleeding and thrombotic risk to the underlying vasculature. Bleeding would be more of an issue with arterial MP while thrombotic risk would likely be more troublesome with venous MP. Larger animal studies are needed to see how this could be scaled up from murine models to patients. As currently performed, MPs are placed within a VP to allow for adjacent graft/scaffold vascularization. It will be interesting to see if MPs within AVLs would have a synergistic effect on promoting scaffold vascularization and studies are ongoing.

All three surgical approaches demonstrate the possibility of modulating angiogenesis through a combination of microhemodynamic alterations and/or inflammation. Both processes have been described in the past as critical to new capillary growth. Because the surgical approaches described are highly modifiable; they may find a niche not just for reconstructive surgery and tissue engineering but also for the entire gamut of ischemic disease.

Building Tissue-Specific Vasculature

Tissue and organ regeneration have significant unmet needs. While advancements have been made, the goal to build rapidly perfusable tissues or organs to aid in reconstruction is still limited. Here, we provide a brief overview of the impact and residual challenges microvascular bioengineering has for tissue and organ replacement.

Reconstructive surgery

Skin

Limitations in skin graft availability and donor site morbidity have led to engineered substitutes ranging from acellularized biomatrices to synthesized materials. Unfortunately, these substitutes still cannot recreate the native skin microvasculature thereby limiting true skin functionality (Fig. 7A).^283,284 Achieving organized vascularization in skin substitutes remains challenging (Fig. 7B).^285–288

FIG. 7.

Skin native vasculature (A) diagram demonstrating the complexity of natural skin, including the capillary loops that provide nutrition to the skin as well as the different plexuses located in different skin cell layers. Skin engineering strategy example (B) showing a microporous dermal-mimetic electrospun scaffold preseeded with fibroblasts to promote tissue regeneration. Image adapted from Bonvallet et al.³¹¹ Adipose vasculature (C) diagram showing adipocytes with orientation with respect to vasculature and lymphatics. Adipose engineering strategy example (D) showing a human decellularized adipose tissue that was processed into an injectable hydrogel mixed with adipose-derived stem cells, suggesting a culture platform for Adipose derived stem cell (ADSCs) delivery. Image adapted from Pu et al.³¹² Bone native vasculature (E) diagram showing the complexity of bone vasculature, including intricacy of the medullary cavity. Bone engineering strategy example (F) showing a bone decellularized extracellular matrix coated on a polycaprolactone/beta-tricalcium phosphate scaffold that was found to have high compressive strength and promote bone regeneration in the defect site as detailed by Bae et al.³¹³ Diagrams (A, C, E) created using BioRender.com. Engineering strategies images (B, D, F) adapted under the terms and conditions of the Creative Commons Attribution (CC BY) license (CC BY 4.0 Deed | Attribution 4.0 International | Creative Commons).

Adipose

The role of fat grafting is well established. However, voluminous reconstruction is still precluded by poor vascularization.^288–290 As native adipocytes develop in parallel to vascular networks (Fig. 7C), emerging approaches in vascularized adipose engineering employ synthetic, natural, and ECM-based scaffolds (Fig. 7D).^291–294 Vascularized adipose TE has had varying success in concurrently promoting angiogenesis and tissue regeneration^295–302; however, challenges still persist.^303–305

Bone

Successful bone reconstruction depends on effective vascularization and the nutrient artery is vital (Fig. 7E).^43,306,307 Diversity in bone structure and tensile force requirements present additional challenges in bone TE. 3D-printed scaffolds and cell seeding have demonstrated variable effectiveness in concurrently promoting microvascular formation and osteogenic differentiation.^308–310 Despite advancements, clinical translation remains challenging (Fig. 7F).

Transplant surgery

Liver

End-stage liver disease causes two million deaths annually³¹⁴ with transplantation being the primary treatment. Organ scarcity mandates TE solutions.^314,315 Liver engineering is particularly challenging because of its unique vascular and sinusoidal network, crucial for filtration and metabolism (Fig. 8A). Techniques such as decellularization and recellularization (Fig. 8B) have shown promise, but are limited by thrombosis and immune reactions. Bioprinting and other methods are also currently being explored to create functional hepatic microvasculature.^316–319

FIG. 8.

Liver native vasculature (A) diagram showing the complexity of the liver vasculature, including the inflow of the hepatic artery and portal vein, with the outflow of the inferior vena cava. Additionally shows the complexity of a liver lobule. Liver engineering attempt example (B) image showing decellularized liver graft adapted from Li et al.³⁴⁸ Kidney native vasculature (C) diagram showing the vasculature of the nephron in relation to the collecting system. Kidney engineering attempt example (D) showing decellularized glomerulus image adapted from Figliuzzi et al.³⁴⁹ Pulmonary native vasculature (E) diagram showing the pulmonary vasculature to the lungs, including the alveoli. Lung engineering attempt example (F) image of decellularized lung ECM-derived scaffold image adapted from Noori et al.³⁵⁰ Diagrams (A, C, E) created using BioRender.com. Images (B, D, F) adapted under the terms and conditions of the Creative Commons Attribution (CC BY) license (CC BY 4.0 Deed | Attribution 4.0 International | Creative Commons).

Kidney

Kidney transplants are a solution for end-stage renal disease but also suffer from donor scarcity. The dense and complex renal microvascular network (Fig. 8C) poses unique TE challenges as the resultant vasculature needs to not only accommodate 20% of cardiac output but also mitigate renin release and filter blood.^53,320 Despite promising advances (Fig. 8D), long-term functionality and thrombosis remain significant obstacles.^53,320–334

Lung

Lung engineering is complicated by the need to replicate a dual circulatory system for effective gas exchange (Fig. 8E). Decellularized scaffolds have been a primary focus, with experiments demonstrating the potential for gas exchange in recellularized lungs (Fig. 8F). However, challenges such as recreation of a functional alveolar-capillary barrier persist, underscoring the need for continued research.^{57,59,335–347}

Conclusion and Future Directions

Despite significant advances in TE, vascularization remains an obstacle in creating truly functional tissue. Because of tissue and organ-specific nuances at the microvascular level, customization is warranted depending on tissue type. Innovative combinatorial engineering and surgical approaches may hold promise in solving the challenges intrinsic to tissue and organ microvascular fabrication.

Authors’ Contributions

D.J.R. conceived the research topic and oversaw the direction, planning, writing, and editing. K.S. performed the literature review and was the primary writer. K.S., M.A., D.A.F.-A., J.C.E.-M., O.W., J.D., S.A., and M.E.L.: all provided critical feedback and editing.

Footnotes

Funding Information

NIH-1R56HL157190-01 (D.J.R.), Dorothy Foehr Huck and J. Lloyd Huck Endowed Chair of the Pennsylvania State University (D.J.R.), Comprehensive Health Studies Collaborative Program Award of the Penn State College of Medicine (D.J.R.).

Disclosure Statement

Authors have no conflict of interest to disclose.

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