How Can Novel Bioactive Glass Wound Matrix Optimise Hard-to-Heal Venous Leg Ulcers

March 2024

How

Can Novel Bioactive Glass Wound Matrix Optimise Hard-to-Heal Venous Leg Ulcers in Geriatric Patients with Multiple Comorbidities?

Editorial Summary

In this retrospective case series, the efficacy of a novel borate-based bioactive glass wound matrix (BGWM) in treating hard-to-heal venous leg ulcers in geriatric patients with multiple comorbidities was evaluated. Patients were selected who had undergone both arterial and venous duplex procedures, with some receiving venous ablation treatments. Prior to BGWM application, wounds were debrided once and cleansed with hypochlorous acid solution. The BGWM was then contoured, tailored and applied directly to the wound bed. The BGWM was secured with a contact layer and skin strips. A super-absorbent fiber dressing was used to manage exudate, and compression dressings were changed twice per week. This retrospective pilot study included patients with an average age of 80.3 years, each presenting with one or more venous leg ulcers and a range of comorbidities. The wounds, present for an average of 15.1 weeks before BGWM application, varied in size from 1.2 to 56.0 cm². Results indicated a significant improvement in wound healing, with all wounds healing within an average of 10 weeks. Pain levels, initially averaged at 5.8/10, were reduced to 0.0/10 after an average of 2.6 dressing changes. The study concluded that BGWM facilitated wound closure, was well tolerated by patients, significantly reduced pain, and did not result in any adverse events or require antibiotics, underscoring its potential as an effective treatment for venous leg ulcers in elderly patients with complex health profiles.

Wound healing impairment represent a significant clinical challenge in geriatric patients. Age-related physiologic changes predispose the elderly to chronic non-healing wounds. Dermal and epidermal thinning along with decreased elasticity of aged skin increases susceptibility to injury and impairs structural integrity.1 Elderly patients also have decreased mobility, circulation, and sensation, which can delay wound healing. Comorbidities prevalent in this population, including restricted mobility, peripheral vascular disease, neuropathy, and immunosenescence further compromise wound healing potential.2 This paper explores the use of a novel borate-based bioactive glass wound matrix (BGWM) , (Mirragen® Engineered Tissue Solutions, MO) which shows promising results in this patient demographic.

Geriatric Patients Face Unique Challenges in Wound Care:

• Poor Circulation

Age-related arteriosclerosis and vascular stiffening lead to diminished peripheral perfusion and tissue oxygenation. The resultant hypoxic state and impaired delivery of circulating nutrients critically disrupt the physiological milieu required for optimal wound healing processes.3 Chronic diseases that affect circulation like peripheral vascular disease or diabetes compound the problem. Strategies like compression stockings can have an impact to blood flow to wound sites.4

• Thin Fragile Skin

The elderly exhibit delayed and disordered repair across all phases of wound healing. Impairments in the inflammatory phase include decreased neutrophil chemotaxis, phagocytosis, and oxidative kill in response to bacterial contamination.3 The proliferative phase is hindered by age-related declines in fibroblast migration, proliferation, and expression of growth factors necessary for angiogenesis and extracellular matrix deposition.4 Finally, re-epithelialization deficits interfere with keratinocyte activation and migration required for re-

Dr Martin L. Johnson

Plastic Surgeon, Wound Care Specialist

Pomona CA, United States

Prof David G. Armstrong

Professor of Surgery and Director, Southwestern Academic Limb Salvage Alliance (SALSA), Keck School of Medicine of USC Los Angeles CA, United States

Ms Erianthe Ortega

Research Nurse, RN-PHN, BSN

Pomona CA, United States

How Can Novel Bioactive Glass Wound Matrix Optimise

“The complex barriers to healing posed by age necessitate a multifaceted, patient-centered approach. BGWM is a is a bioabsorbable wound matrix composed of borate-based glass fibers. Its composition and structural properties have been intentionally engineered to exhibit biocompatibility and facilitate the body’s innate wound healing cascades. Preclinical and clinical evaluations have demonstrated this matrix to be a safe, effective and efficient therapeutic modality for the management of both acute traumatic wounds as well as complex chronic wound etiologies.”

epithelialization.5

• Impaired Immunity

Chronic wounds in the geriatric population are often complicated by multiple intrinsic and extrinsic factors. Venous stasis ulcers and diabetic foot ulcers are among the most common etiologies.6 These nonhealing wounds significantly impact quality of life, increase risk of infection, amputation, and consume substantial healthcare resources.7 Optimizing local wound care and addressing systemic factors like malnutrition, glycemic control, and vascular insufficiency are crucial to facilitate healing in this challenging patient subset. Older adults are also at increased risk of wound infections, which can quickly become systemic.7 Meticulous wound care technique and early treatment with oral antibiotics combat infections.

• Nutritional Deficits

Sufficient protein intake and adequate levels of micronutrients such as vitamins A, C, and zinc are essential requirements for appropriate tissue repair and regenerative processes. Nutritional deficiencies, often seen in the geriatric population due to poor dietary intake or malabsorptive states, can significantly impair wound healing capabilities. Targeted nutritional supplementation with high-calorie, highprotein oral formulations enriched with zinc and vitamin complexes may help restore the metabolic derangements that compromise the body’s reparative mechanisms in this vulnerable patient subset.

• Reduced Mobility

Mobility limitations prevalent in the geriatric population critically impede their ability to perform necessary

offloading maneuvers and regular dressing changes for existing wounds. Failure to periodically redistribute pressure and alleviate persistent compression leads to the development of additional pressure injuries. Involvement of skilled nursing personnel to provide comprehensive wound care, including adherence to rigid repositioning schedules, is paramount in preventing further cutaneous deterioration and preserving the integrity of tissues overlying bony prominences in this highrisk cohort.8

The complex barriers to healing posed by age necessitate a multifaceted, patient-centered approach. Individualized nutritional support, infection control, advanced dressings, and pressure redistribution are key elements in effective geriatric wound management. With proper treatment, even chronic wounds can be healed, dramatically improving seniors’ quality of life.

Early intervention to return hard-to-heal wounds to a healing trajectory is crucial in improving wound care efficiency.9 Once the patient’s underlying conditions are addressed, there is enhanced benefit for use of advanced products that target specific wound problems. Use of a recently developed novel boratebased bioactive glass wound matrix* (BGWM) has demonstrated promise in wound healing.10 This bioactive glass fiber has been shown to stimulate soft tissue growth and angiogenesis, and to reduce inflammation and incidence of infection.11-13 Bioactive glass materials are biocompatible water-soluble materials that release their ions when submerged in body fluids. We report our experience with application of BGWM in venous leg ulcers of patients with multiple comorbidities.

Arterial and Venous Duplex Procedures

Duplex ultrasonography is an essential vascular

study for older adults with compromised circulation. This non-invasive test uses Doppler ultrasonography to visualize blood flow in arteries and veins.

For arterial exams, duplex imaging assesses blood flow volume and velocity to identify blockages or narrowing. Testing of lower extremity arteries helps diagnose peripheral artery disease, a common contributor to poor wound healing in the elderly. However, preexisting wounds may preclude compression which is necessary for valid testing.

Venous duplex scans evaluate blood flow, valve competency, and potential clots in leg veins. Chronic venous insufficiency impedes venous return, causing edema and venous leg ulcers.14 Ultrasound mapping locates faulty valves needing repair. But for accurate results, wounds must be completely dry with dressings removed, which risks contamination or trauma to fragile surrounding tissues.

While vascular duplex provides key data to guide treatment, wound issues like infection or fragility may restrict proper scanning. Clinicians must carefully weigh the risks and benefits of testing, and take precautions to avoid aggravating wounds. With thoughtful preparation and technique, duplex can successfully inform vascular interventions to improve tissue perfusion and healing in the vulnerable elderly population.

Venous ablation is a minimally invasive technique that uses thermal energy to seal faulty veins causing venous insufficiency.15 While an effective option for younger patients, several factors make venous ablation more complex in the elderly.

Age-related Dermal Atrophy and Thermal Injury Risk During Endovenous Ablation

The geriatric population exhibits dermal and subcutaneous tissue atrophy, resulting in decreased adipose insulation surrounding superficial leg veins targeted for endovenous thermal ablation procedures. This attenuation of the protective soft tissue layer overlying the venous structures increases the risk of iatrogenic thermal injury to surrounding skin and subcutaneous tissues during the application of tumescent anesthesia and heat-based ablative energies.

Leg Ulcers

Consequently, stricter temperature parameters and temporal limitations must be implemented during endovenous heat delivery in elderly patients undergoing these procedures. Establishing more conservative maximum temperature thresholds and curtailing the duration of thermal exposure are prudent measures to mitigate the heightened vulnerability to cutaneous burns and deeper soft tissue thermal necrosis in this specific patient subset with compromised anatomic insulation.

•

Impact of Comorbidities on Procedural Risks

Coexisting medical conditions highly prevalent in the geriatric population, such as diabetes mellitus, peripheral vascular disease, and chronic edematous states, further compound the risk profile for potential wound complications associated with endovenous thermal ablation procedures. To mitigate these heightened risks, a more judicious approach to selecting more favorable venous targets and implementing conservative limitations on the extent and magnitude of delivered ablative energy is warranted in elderly patients with these comorbidities.

•

Pharmacological Considerations

This patient subset also exhibits an exaggerated sensitivity to sedative and analgesic medications frequently employed during these procedures. Appropriate downward dosage adjustments are therefore requisite to avoid excessive central nervous system depression. Maintaining a relatively lighter plane of sedation allows for continuous monitoring of the patient’s pain perception and facilitates early detection of potential iatrogenic thermal injury during the ablation.

• Cognitive and Mobility Factors

Cognitive deficits associated with neurodegenerative disorders may impair some elderly patients’ capacity to comprehend and comply with critical procedural instructions, such as maintaining immobility during the application of ablative energy. Finally, age-related decrements in mobility and

How Can Novel Bioactive Glass Wound Matrix Optimise

dexterity commonly afflict the geriatric population, potentially hampering their ability to properly apply and maintain therapeutic compression stockings during the post-procedural period. Transitioning to alternative compression modalities, such as adhesive multi-layer compression bandages or adjustable circumferential compression devices, may enhance selfcare capabilities and improve compliance with this critical aspect of post-ablation management.

With thoughtful precautions including lower energy settings, mild sedation, compression alternatives, and careful monitoring, ablation can still successfully treat venous reflux in elderly patients. However, risks versus benefits must be weighed carefully for each individual. Improved collaboration with geriatrics teams helps optimize outcomes.

In health, the venous system of the lower leg pumps blood back towards the heart. This action, performed against gravity, is facilitated by three categories of veins: deep, superficial, and communicating (perforator) veins. The superficial veins, including the long and short saphenous veins, pump blood under low pressure into the deep venous system through perforators. The deep veins, surrounded by calf muscles, assist in pumping blood up the leg during walking, aided by the calf muscle pump and full ankle movement, which engages the Achilles tendon.

Damage to the venous system can arise from various conditions, such as deep vein thrombosis and varicose veins, which damage the perforators and make them incompetent.

Additionally, immobility and arthritic changes in the ankle joint can impede venous return. Failure of the calf muscle pump leads to blood backflow and pooling, resulting in venous hypertension. This condition causes edema in the lower leg and pigmentation in the ‘gaiter’ area due to hemoglobin released from overstretched blood capillaries, depositing haemosiderin. The increased ambulatory pressure may also increase the permeability of the capillary bed, allowing fibrinogen to escape into the interstitial fluid, forming insoluble fibrin complexes that hinder oxygen diffusion to tissues, a condition described by the ‘fibrin cuff theory.’

Other causative theories include the ‘white cell trapping’ theory, suggesting that white cells, following an episode of deep vein thrombosis or phlebitis, become trapped in the leg’s capillaries. These cells then release toxic substances like oxygen free radicals, causing tissue death. Such underlying issues become evident when any subsequent minor injury to the lower leg area can rapidly lead to ulceration. Venous leg ulcerations (VLU) most commonly occur around the gaiter area, where the ulcers tend to be shallow.16

When examining wounds in elderly patients, it is important to move slowly and communicate clearly. Elderly skin is thinner and more fragile, so handle the surrounding area gently. Assess the wound for signs of infection like redness, swelling, drainage, odor, and pain. Consider factors that may delay healing such as poor circulation, nutrition, and mobility. The elderly are at higher risk for skin tears so check carefully for flap tears if tape or bandages are removed. Evaluate the wound bed for necrosis or eschar formation. Check sensation around the wound for neuropathy which can increase risk. Assess medical history including medications that may interfere with healing. Explain what you are checking for at each step to help ease anxiety. Keep in mind recovery may be slower so set realistic goals, and follow up more frequently on progress. With patience and care, you can properly examine and treat wounds in the elderly population.

Methods

Patient Selection and Pretreatment Evaluation

All patients enrolled in this study underwent comprehensive vascular assessment with arterial and venous duplex ultrasound examinations prior to initiation of treatment. In addition, 3 of the 5 patients had previously undergone venous ablation procedures to treat associated venous insufficiency.

Wound Preparation

At baseline, all wound beds were sharply debrided to remove devitalized tissue and create an appropriate environment for wound healing. No patients received systemic antibiotic therapy during the study period. Wound cleansing prior to each bioengineered graft application consisted of irrigation with a hypochlorous acid solution to reduce bacterial burden.

How Can Novel Bioactive Glass Wound Matrix Optimise Hard-to-Heal Venous Leg Ulcers

Bioactive Matrix Application

The Bioactive Wound Matrix (BGWM) was prepared by trimming to the dimensions required to fully cover the wound area, ensuring a 3-4 mm overlap onto the peri-wound skin. The customized BGWM was then placed in direct contact with the wound bed and immobilized using an adhesive contact layer reinforced with skin strips. A super-absorbent fiber dressing was applied as an outer layer to manage wound exudate. Compression wraps consisting of two layers were applied over the dressings and changed twice weekly at each study visit along with inspection and reinforcement of the underlying BGWM application as needed.

This structured wound care protocol following

established clinical practice guidelines was implemented consistently across all patients to ensure standardization of the bioactive graft application technique.

Results

Five patients with six venous leg ulcers were treated. Average patient age was 80.3 (range: 6887) and all patients had multiple comorbidities. Wounds were present an average of 15.1 weeks prior to initial BGWM application and mean wound size at start of BGWM was 13.5 cm2 (range: 1.2-56.0 cm2). All wounds healed after an average of 10.0 weeks (range: 3-27 weeks) during use of BGWM. Pain on a self-reporting scale was reduced from an average of 5.8/10 to 0.0/10 within an average of 2.6 dressing changes.

Figure 1a:

Patient with large, right medial, non-healing lower leg defect shown

Figure 1b:

Patient showing healed, right medial lower leg defect after BGWM application

Figure 2a:

Patient with large, non healing medial leg wound, resistant to other treatment modalities

Figure 2b:

Patient showing anterior view of nearly healed medial leg wound after BGWM

Figure 3a:

Patient with left medial leg non healing wound

Figure 3b:

Patient with almost complete closure after BGWM application

Figure 4a:

Patient with non healing, arm wound

Figure 4b:

Patient with healed wound after BGWM application

How Can Novel Bioactive Glass Wound

Discussion

The results of this case series demonstrate the potential efficacy of using a bioactive graft wound matrix (BGWM) for treating chronic venous leg ulcers in an elderly patient population with multiple comorbidities. The ability to achieve complete wound closure in all 6 ulcers after an average of 10 weeks of BGWM application is noteworthy, especially considering the ulcers had been present for an average of 15.1 weeks prior to starting BGWM and were previously non-healing.

The mean initial ulcer size of 13.5 cm2 indicates that many of the wounds were quite large, yet the BGWM facilitated healing even for the largest 56 cm2 ulcer. This suggests BGWM may be effective for a range of wound sizes and severity. Additionally, the short median healing time of 10 weeks compares favorably to expected healing times with standard wound care.

The rapid and significant pain reduction reported by patients is another clinically relevant benefit observed with BGWM use. Decreasing pain from a mean of 5.8/10 down to 0/10 within just 2-3 dressing changes likely improved patient quality of life and willingness to continue treatment. Chronic wound pain can be challenging to manage.

From a clinical workflow perspective, the ease of BGWM application and ability to use it until full closure without requiring frequent dressing changes is advantageous. The lack of need for systemic antibiotic therapy is also noteworthy

given concerns over antimicrobial resistance.

Mechanistically, the bioactive graft matrix likely provided the well-vascularized wound bed with a scaffold to facilitate cell migration, attachment, and proliferation of key cell types like fibroblasts and keratinocytes. BGWMs are designed to be gradually remodeled and resorbed as the patient’s own extracellular matrix is deposited.

Limitations of this study include the small sample size, lack of a control group, and possible selection bias towards patients felt to be good candidates for BGWM. However, these promising pilot results support further investigation of BGWM in a larger, controlled trial, potentially comparing it to other advanced wound care products. Cost-effectiveness analysis would also be valuable given the expenses associated with chronic wound care.

In conclusion, this case series provides early evidence that a bioactive graft wound matrix may represent an effective tool for treating recalcitrant venous leg ulcers in a complex patient population. The ability to achieve full wound closure, provide rapid pain relief, avoid systemic antibiotics, and streamline dressing changes are all clinically relevant advantages observed. Larger, controlled studies are still needed to better evaluate the safety and efficacy profile of BGWM compared to standard treatments and other advanced wound matrices. But these initial results are promising for this novel wound care approach.

Figure

How Can Novel Bioactive Glass Wound Matrix Optimise Hard-to-Heal Venous Leg Ulcers

BGWM is a bioabsorbable wound matrix composed of borate-based glass fibers. Its composition and structural properties have been intentionally engineered to exhibit biocompatibility and facilitate the body’s innate wound healing cascades. Preclinical and clinical evaluations have demonstrated this matrix to be a safe, effective and efficient therapeutic modality for the management of both acute traumatic wounds as well as complex chronic wound etiologies.

The borate-based glass fiber construct provides a conducive three-dimensional scaffold to support the coordinated phases of wound repair. It allows for optimal cellular infiltration, migration, and proliferation of key cell types like fibroblasts, keratinocytes, and endothelial

References

1. wcw-admin-support. “What Slows Wound Healing in Older Patients: Effects of Age.” West Coast Wound & Skin Care, 31 July 2022, westcoastwound.com/what-slows-wound-healing-in-older-patients/

2. Anderson, Kristin, and Rose L. Hamm. “Factors That Impair Wound Healing.” Journal of the American College of Clinical Wound Specialists, vol. 4, no. 4, Dec. 2012, pp. 84–91, https://doi.org/10.1016/j.jccw.2014.03.001.

3. Zemaitis, Michael R, et al. “Peripheral Arterial Disease.” Nih.gov, StatPearls Publishing, 23 May 2023, www.ncbi.nlm.nih.gov/books/NBK430745/

4. Shi, Chunhu, et al. “Compression Bandages or Stockings versus No Compression for Treating Venous Leg Ulcers.” Cochrane Database of Systematic Reviews, vol. 2021, no. 7, 26 July 2021, https://doi.org/10.1002/14651858.cd013397.pub2

5. National Clinical Guideline Centre (UK). “Barrier Creams.” Nih.gov, National Institute for Health and Care Excellence (UK), Apr. 2014, www.ncbi.nlm.nih.gov/books/NBK333167/

6. Weyand, Cornelia M., and Jörg J. Goronzy. “Aging of the Immune System. Mechanisms and Therapeutic Targets.” Annals of the American Thoracic Society, vol. 13, no. Supplement_5, Dec. 2016, pp. S422–S428, https://doi.org/10.1513/annalsats.201602-095aw

7. Gould, Lisa, et al. “Chronic Wound Repair and Healing in Older Adults: Current Status and Future Research.” Journal of the American Geriatrics Society, vol. 63, no. 3, Mar. 2015, pp. 427–438, https://doi.org/10.1111/jgs.13332

8. Pickham, David, et al. “Evaluating Optimal Patient-Turning Procedures for Reducing Hospital-Acquired Pressure Ulcers (LS-HAPU): Study Protocol for a Randomized Controlled Trial.” Trials, vol. 17, no. 1, 6 Apr. 2016, https://doi.org/10.1186/s13063-016-1313-5

cells. Concomitantly, the gradual resorption and remodeling of the bioabsorbable matrix facilitates deposition and integration of the patient’s own extracellular matrix proteins.

This biomaterial exhibits advantageous antimicrobial properties while maintaining a physiologically moisture-balanced wound environment conducive to healing. Its inherent flexibility and conformability enable excellent adhesion to the wound bed and periwound area. When applied with appropriate wound bed preparation, the borate glass matrix provides an advanced wound care solution that synergistically augments the body’s reparative mechanisms for a diversity of wound presentations across the entire continuum of acute to chronic wound chronicity.

9. Milne J, Searle R, Styche T. The characteristics and impact of hard-to-heal wounds: results of a standardized survey. J Wound Care 2020;29:282-288.

10. Armstrong DG, Orgill DP, Galiano RD, et al. A multi-centre, single-blinded randomised controlled clinical trial evaluating the effect of resorbable glass fibre matrix in the treatment of diabetic foot ulcers. Int Wound J. 2022 May;19(4):791-801.

11. Jung S, Day T, Boone T, et al. Anti-biofilm activity of two novel, borate based, bioactive glass wound dressings. Biomed. Glasses 2019; 5:67–75.

12. Rahaman MN, Day DE, Bal BS, et al. Bioactive glass in tissue engineering. Acta Biomater. 2011; 7(6): 2355–2373.

13. Mehrabi T, Mesgar AS, Mohammadi Z. Bioactive Glasses: A Promising Therapeutic Ion Release Strategy for Enhancing Wound Healing. ACS Biomater Sci Eng. 2020;6(10):53995430.

14. Oľga Križanová, et al. “Chronic Venous Insufficiency and Venous Leg Ulcers: Aetiology, on the Pathophysiology‐Based Treatment.” International Wound Journal, 19 Oct. 2023, https:// doi.org/10.1111/iwj.14405.

15. Octavian Andercou, et al. “Radiofrequency Thermal Ablation for the Treatment of Chronic Insufficiency of the Saphenous Vein—a Comparative Retrospective Study.” International Journal of Environmental Research and Public Health, vol. 20, no. 4, 14 Feb. 2023, pp. 3308–3308, https://doi.org/10.3390/ijerph20043308.

16. Probst, Sebastian. Wound Care Nursing : A Person-Centred Approach. 3rd ed., Amsterdam, Elsevier, 2020.