NIH funding opportunities (2) – Non-healing Ulcerative Wounds in Aging (R01, R21)

May 10, 2016 by School of Medicine Webmaster

The description below was taken from the R01 version of this FOA.

Ulcerative wounds, including venous leg ulcers, diabetic foot ulcers and pressure ulcers, occur more commonly in older adults and their impaired healing is associated with underlying and comorbid diseases of aging, and defects of wound repair. The incidence of chronic wounds increases with age from the sixth to the ninth decades.  Delayed wound healing increases the risk of recurrent infection and tissue necrosis.  This results in substantial morbidity, disability, hospitalization, and even mortality among older adults.

Recently, care improvements have been observed for diabetic foot ulcers, with a resulting decline in the rates of lower-extremity amputation among persons with diabetes, but there are significant lags among persons age 75+ years, blacks and men.  However, amputation rates among the non-diabetics did not change, indicating a lack of improvement in the management of other types of foot ulcers.  Research into the basic science of wound healing, translational research and development and evaluation of novel clinical approaches may be beneficial to develop understanding and improve the health outcomes of chronic wounds among persons who are aging.

Wound healing and restoration of an intact skin barrier is a complex process involving the coordinated response of several cell types including fibroblasts, endothelial cells, macrophages, platelets and keratinocytes. Although understanding of the processes that lead to resolution of a wound has improved, few studies have explored how aging impacts these processes and this gap in our understanding may limit the applicability of novel therapies for wound resolution in older persons. Migration, infiltration and differentiation of these cells are regulated by a signaling network involving many different growth factors and cytokines. Aging processes appear to be associated with dysfunctional cellular responses leading to impaired tissue remodeling and delayed wound resolution.  Also, pathologic tissue fibrosis may result from dysregulation of normal wound healing processes. Therefore, tissue aging appears to contribute to the formation of a wound site that is unable to heal properly.

Recent advances in the understanding of the wound-healing process have led to innovative clinical approaches to wound care including the use of stem cells, growth factors and bioactive materials to support the body’s own regenerative capacity. However, the relevant specialty societies that have developed ulcerative wound treatment guidelines lack a strong consensus on the optimal multicomponent treatment approach, with the exception of using dressings and compressions. The guidelines have been largely based on expert opinion, so better evidence is needed.

Though several efficacy endpoints are discussed in an active Food and Drug Administration guidance, complete wound closure of a chronic, non-healing wound is singled out as one of the most objective and clinically meaningful endpoints.

Improved care of chronic ulcerative wounds could reduce morbidity and mortality.  Translational studies may be developed for novel cellular products, immune modulation, microbiome-modifying therapy, human tissue, animal-derived tissue, biosynthetic products, other strategies including exercise/physical therapy, and nutritional interventions.  Certain wound therapies might be applied consistently to all patients, including dressings, compression, off-loading, and debridement.

A 2014 NIA-sponsored U13 workshop on chronic wound repair and healing recommended the development of evidence-based therapy in the clinic, adopting improved trial design, defining standard wound care, and choosing appropriate trial endpoints for evaluating wound therapies. Transdisciplinary approaches to collaboration were recommended to improve the translation of the basic science findings into improved wound care approaches.  The workshop summary was published in two journals, J Am Geriatr Soc. 2015 Mar;63(3):427-38 and Wound Repair Regen. 2015 Jan-Feb;23(1):1-13.  A 2012 NIA workshop had made consistent recommendations about studying wound biology and about the relevance of various aged animal models as experimental systems to address key gaps in our understanding of factors that contribute to delayed wound healing in aged tissues. In addition, recent Cochrane reviews and technology assessments have identified the characteristics of ideal studies that might be employed to evaluate the multi-component strategies for treating chronic wounds.  Important features include standardizing treatment protocols, including patients with a specific type of wound, defining and using an objective measure for complete wound healing, and adequate follow-up of patients.

Specific Areas of Research Interest

This FOA will support basic and translational clinical research to identify the critical defects in the wound healing process in aged tissues and persons and test clinical interventions for safety and effectiveness.

This FOA particularly invites research applications in animal models and/or in humans, addressing the etiology, pathophysiology, risk factors, consequences, prevention, or treatment of non-healing ulcerative wounds including venous leg ulcers, diabetic foot ulcers and pressure ulcers. Areas of interest and potential research questions include, but are not limited to those listed below:

Biology, Etiology and Pathophysiology

  • Basic and late-stage translational research conducted in aged animal models using model systems that have been validated previously to further elucidate the essential mechanisms in the wound healing processes that are dysregulated with aging and which might lead to new therapeutic approaches to combat delayed wound healing in the elderly.
  • What causes acute injuries to become chronic wounds?
  • What factors regulate or activate macrophage phenotypes in wound repair?
  • What are the roles of proliferation and apoptosis in acute versus chronic wounds?
  • What are the contributions of aging and comorbidities to the development of chronic wounds?
  • What is the optimal inflammatory response that will support rapid repair yet effectively reduce infection?
  • Which microbiota are beneficial, and which are problematic for wound healing?
  • How does microbial bioburden in the wound influence systemic and local immune responses?
  • How does age influence microbial burden in wounds and subsequent wound healing?

Translation into Clinical Research

  • Translational strategies may include but are not limited to:  cellular products, immune modulation, microbiome-modifying therapy, human tissue, animal-derived tissue, biosynthetic products, and other strategies including exercise/physical therapy, nutritional interventions and multicomponent approaches.  Certain wound therapies might be applied consistently to all patients, including dressings, compression, off-loading, type and timing of debridement.
  • What interventions effectively improve microcirculation and wound healing with aging?
  • How do various wound treatments affect microbial burden?
  • What new therapeutics can be developed based on the microbiome?
  • How should cellular therapy be positioned in wound care?
  • What potency assays are available to regulate cellular therapies?
  • What is the effectiveness of physical modalities such as electrical stimulation and ultrasound in older adults?
  • Design and conduct of clinical trials of multi-component strategies for treating chronic non-healing ulcerative wounds among predominantly older adults using a primary outcome of complete wound closure or other clinically meaningful endpoint.

Diagnosis, Prevention and Management

  • What interventions effectively prevent chronic wounds in older adults?
  • What is the effect of wound therapies on universal outcomes, such as functional status, pain, physical impairment, mobility, and cognitive impairment, as opposed to wound-specific outcomes?
  • What is the effect of multicomponent interventions on individual- and wound-specific outcomes?
  • Are there special considerations related to older adults with chronic wounds and dementia?
  • During surgery, what steps can anesthesiologists take to mitigate risk for chronic or nonhealing wounds?
  • Can individuals be better categorized on the spectrum from cachexia to starvation, and can this categorization aid in determining the most-effective nutritional treatment strategies for persons with chronic wounds?
  • What is the optimal protein and energy intake for older adults with chronic wounds, especially at weight extremes?
  • Is there a role for complete and various modular nutritional supplements, vitamin and mineral supplementation above the U.S. recommended daily intake, or appetite stimulants and anabolic steroids in the care of individuals with chronic wounds?
  • What is the effect of wound-associated pain on quality of life and function?
  • What are the effects of other comorbidities in conjunction with chronic wounds, with respect to quality of life?
  • What are the effects of socioeconomic status, living status, and other social factors on chronic wounds and quality of life?

Specific to NINR:  NINR is primarily interested in:

  • Clinical research that addresses chronic wounds (development, progression, healing, and recurrence) and associated symptoms (e.g., pain, burning, itching); and
  • Behavioral interventions aimed at preventing the onset of chronic wounds, expediting the healing process, alleviating wound-related symptoms, promoting self-management strategies, and improving quality of life.

Deadlines:  standard dates apply


Filed Under: Funding Opportunities