Clinical Achievement of Wound Closure and Tissue Quality With a Novel Microvascular Tissue Graft

Introduction. Microvascular tissue serves as the foundation for tissue granulation and remodeling during the wound healing process. Optimal repair of microvascular structure and function is essential for future healing capacity and to minimize tissue breakdown in a newly epithelialized wound. Objective. This case series of 3 patients with nonhealing diabetic foot ulcers (DFUs) refractory to standard wound care demonstrates the ability of processed microvascular tissue (PMVT) to enable wound closure, increase local perfusion and vascular maturity, and improve overall tissue quality. Materials and Methods. Three patients with nonhealing DFUs ranging from 1.1 cm² to 11.2 cm² recalcitrant to standard of care were treated weekly with topical PMVT and standard of care. Wound closure was measured weekly using infrared imaging. Fluorescence microangiography was used to perform dynamic quantification of wound microcirculation and assess the perfusion quality. Ingress rates were measured at 5 defined rectangular regions of interest of the wound to evaluate inflammation and microvascular integrity. Results. All 3 nonhealing DFUs treated with weekly topical PMVT healed within 12 weeks (average, 6.3 ± 5.5 weeks). Assessment of healed wounds at the time of closure indicated PMVT treatment significantly improved perfusion within the newly healed wounded area and throughout the immediate surrounding tissues. No wound recurrence or tissue deterioration has been observed in more than 9 months of follow-up. Conclusions. In this series of patients, the PMVT graft demonstrated improved wound closure, increased local perfusion and vascular maturity, and improved tissue quality. This graft is a promising advanced tissue therapy for nonhealing DFUs and other complex wounds. It is now the subject of a randomized controlled trial.

The quality of healed tissue is frequently overlooked in clinical trials that primarily focus on rate and incidence of wound closure. Microvascular tissue serves as the foundation for granulation and remodeling during healing. Optimal restoration of microvascular structure and function is essential for healing and to mitigate tissue vulnerability in a newly epithelialized wound. This is especially true when the tissue microenvironment is compromised by advanced age, diabetes, small vessel disease, or radiation. 

A novel processed microvascular tissue graft (PMVT; mVASC; MicroVascular Tissues, Inc., San Diego, CA) contains multiple biological factors and structures capable of stimulating tissue repair, regeneration, and angiogenesis.^1-3 Multiplex enzyme-linked immunosorbent assay characterization of PMVT has shown a significant presence of numerous proteins,¹ including platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factors 1 and 2, and stromal cell-derived factor 1. 

This paper aims to demonstrate the ability of PMVT to enable wound closure, increase local perfusion and vascular maturity, and improve overall tissue quality in 3 clinical cases of nonhealing diabetic foot ulcers (DFUs) refractory to standard wound care.

Three patients presented to the Foot and Ankle Associates of Southwest Virginia (Roanoke, VA) with nonhealing DFUs ranging from 1.1 cm² to 11.2 cm² recalcitrant to standard care (cleaning, debridement, application of a nonadherent dressing, and offloading) and were treated weekly with topical PMVT and standard care. Wound closure was measured using infrared imaging (inSight; eKare Inc, Fairfax, VA). Fluorescence microangiography (LUNA; Stryker Corporation, Kalamazoo, MI) was used to perform dynamic quantification of wound microcirculation and assess perfusion quality. Lower rates of ingress in fluorescence microangiography intensity images (demonstrated by blue hues) correspond to the maturation of the surrounding vasculature and increase in tissue perfusion, oxygenation, and overall tissue quality. Ingress rates were measured at 5 defined rectangular regions of interest, including 1 region at the center and 4 regions around the periphery of the wound, to evaluate inflammation and microvascular integrity.

In this case series, all 3 nonhealing DFUs treated with weekly topical PMVT healed within 12 weeks (average, 6.3 ± 5.5 weeks). Driven by the PMVT graft treatment, the ingress rate measured by fluorescence microangiography decreased from an average of 10.9 ± 4.7 to 2.5 ± 0.9, an average decrease of 77% across the cases.

Case 1
An 85-year-old woman, with a history of high cholesterol, bilateral foot neuropathy, type 2 diabetes, and a previous Charcot condition on her right foot, presented with a right plantar midfoot DFU measuring 1.1 cm², which had not healed after > 5 weeks of standard treatment. With a weekly topical PMVT graft application, the ulcer closed 6 weeks after initial treatment, and remained closed after 8 months post healing. Fluorescence microangiography images and measurements pre- and posttreatment revealed a decrease in wound size correlating to the ingress rate as shown in Figure 1. 

Case 2
A 37-year-old woman, with a history of smoking, hypertension, bilateral foot neuropathy, type 2 diabetes, depression, and congestive heart failure, presented with a left plantar hallux DFU measuring 1.8 cm², which had not healed after 4 weeks of standard treatment. The ulcer closed 1 week after initial PMVT graft application. The wound has remained closed more than 18 months post healing. Fluorescence microangiography images and measurements pre- and posttreatment revealed a decrease in wound size correlating to the ingress rate as shown in Figure 2. 

Case 3
A 65-year-old man, who was a former tobacco user with a history of hypertension, bilateral foot neuropathy, and type 2 diabetes, presented with a wraparound right dorsal, medial, and plantar DFU measuring 11.2 cm², which had not healed after 3 months of standard treatment and also had an active Pseudomonas infection. With weekly topical PMVT applications, the ulcer closed 12 weeks after initial treatment and remained closed 9 months after initial treatment. Fluorescence microangiography images and measurements pre- and posttreatment revealed a decrease in wound size correlating to the ingress rate as shown in Figure 3.

The recognition that microvascular tissue may be a feasible starting source for a cell- or tissue-based therapy has been explored by both McDaniel et al⁴ and Laschke and Menger.⁵ In their work,^4,5 viable microvascular fragments were found to exhibit high proliferation rates and the ability to form capillary networks. The PMVT graft contains nonviable microvascular fragments with a multitude of active tissue repair factors that may provide benefits of angiogenic and tissue healing signaling effects, while the graft’s microvascular structure serves as an extracellular matrix conduit for revascularization. In all 3 presented cases, the decrease in wound size correlated to the ingress rate. Treatment of nonhealing DFUs with the PMVT graft increased local perfusion, as demonstrated by fluorescence microangiography, which in turn led to the formation of granulation tissue and, ultimately, reepithelialization. In 1 particularly complex large DFU with multiple comorbidities, including an active Pseudomonas infection (case 3), weekly topical PMVT applications overcame these challenges and healed the wound in 12 weeks. This case series represents the first publication of clinical utility of PMVT to close hard-to-heal chronic wounds.

The PMVT graft demonstrated the ability to drive wound closure, increase local perfusion and vascular maturity, and improve tissue quality in a series of previously stalled DFUs that failed to close with standard care treatment. Processed microvascular tissue is a promising advanced tissue therapy for nonhealing DFUs and other complex wounds and is now the subject of a randomized controlled trial.

Authors: Charles M. Zelen, DPM¹; Lisa J. Gould, MD, PhD²; and William W. Li, MD³

Affiliations: ¹Professional Education and Research Institute, Roanoke, VA; ²South Shore Hospital, Weymouth, MA; and ³The AngioGenesis Foundation, Cambridge, MA

Correspondence: Charles M. Zelen, DPM, Professional Education and Research Institute, 222 Walnut Ave SW, Roanoke, VA 24016; cmzelen@periedu.com

Disclosure: The processed microvascular tissue graft was provided by MicroVascular Tissues, Inc. (San Diego, CA). Dr. Zelen and Dr. Gould are clinical investigators for MicroVascular Tissues, Inc. Dr. Li is a consultant to MicroVascular Tissues, Inc. Data were presented as a poster at the 2018 Symposium on Advanced Wound Care Fall in Las Vegas, NV.