Combination of Activated Protein C and Topical Negative Pressure Rapidly Regenerates Granulation Tissue Over Exposed Bone to Heal Recalcitrant Orthopedic Wounds

Abstract

Chronic wounds arising from orthopedic surgery present a major clinical challenge. Osteomyelitis may develop from polymicrobial infection, which can be unresponsive to treatment and lead to amputation. Topical negative pressure (TNP) is an effective treatment in wound management and is now used worldwide. Activated protein C (APC) is an anticoagulant with cytoprotective and healing properties. The aim of this study was to determine whether combined treatment of TNP and APC was tolerated and was efficacious for treatment of difficult-to-treat wounds. Four patients who presented to Royal North Shore Hospital with wounds that were not responsive to conventional therapy were studied. All cases showed a marked reduction in wound size and depth within 1 week of starting treatment and progressively improved over time. There was a remarkable increase in the volume of granulation tissue. After treatment, wounds either completely closed or provided sufficient granulation tissue to allow split-thickness skin grafting. The treatment was well tolerated, and the patients were able to be managed on out-patient basis. Long-term follow-up suggested that this treatment prevented osteomyelitis. This innovative treatment is very promising and may significantly increase quality of care for patients with recalcitrant orthopedic wounds. A randomized, placebo-controlled double blind trial is required to further determine the efficacy of APC plus TNP.

Use of dermal injection of activated protein C for treatment of large chronic wounds secondary to pyoderma gangrenosum

“…There is growing evidence that APC accelerates cutaneous wound healing in diabetic and venous ulcers, and in orthopaedic wounds . In the current study, we found that APC showed efficacy for PG wounds in two patients.…”

Inflammation in Chronic Wounds

“…A notable example is activated protein C (APC), which was first discovered for its more well-known activities in anticoagulation but has since demonstrated potent pleiotropic anti-inflammatory and cytoprotective properties [83]. A number of preclinical and pilot clinical trials have demonstrated very promising results to support APC’s use in chronic wounds [84,85,86,87,88,89,90,91]. …”

Activated protein C (APC) can increase bone anabolism via a protease-activated receptor (PAR)1/2 dependent mechanism

“…In a randomized double‐blinded placebo‐controlled trial, APC improved healing of lower leg ulcers, and this was associated with reduced inflammation and increased angiogenesis and epithelialization . Improved wound healing was also seen when topical APC was clinically applied to patients with enduring orthopedic wounds complicated by osteomyelitis . APC has been shown to stimulate osteoblast proliferation via activation of ERK1/2, and increase collagen I expression, ALP activity, and extracellular matrix mineralization in MG‐63 cells .…”