Influence of Comorbidities: Neuropathy, Vasculopathy, and Diabetes on Healing Response Quality

Abstract

Significance: Prolonged and nonhealing connective tissue injuries are often seen associated with common diseases, such as metabolic disorders, obesity, hypertension, arteriosclerosis, neuropathy, and diabetes mellitus and these influences result in considerable burden on society via the health care system, the economy, and quality of life for patients.

Recent advances: Emerging findings have established important new links in our understanding of effective connective tissue healing. Thereby, the function of the nervous system, vascular supply, and metabolic state of the patient can be directly linked to the quality of the connective tissue healing process.

Critical issues: As some of these conditions are also more common in individuals as they age, and aging can also impact healing effectiveness, such complications will have an emerging significant impact as the demographics of many societies change with expanding percentages of the populations >60-65 years of age.

Future directions: Comorbidities have to be early identified in patients with acute wounds or planned surgery. Necessary interactions between physicians with different subspecialties have to be initiated to optimize wound healing potentials.

Paul W. Ackermann, MD, PhD

Figure 1.

(A, B) Immunofluorescence micrographs of sections of tendon tissue after capsaicin denervation (B) and controls (A) after incubation with antisera to Substance P (SP). Arrows denotes varicosities and nerve terminals. A marked reduction of SP immunoreactivity is seen in the denervated group (A, B). Reprinted with permission from Bring et al. v, blood vessel; t, proper tendon tissue. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 2.

(A–C) Overview micrographs of longitudinal sections through the Achilles tendon. Incubation with antisera to general nerve marker PGP 9.5. Micrographs depict the proximal half of the Achilles tendon at increasing magnification. Arrows denote varicosities and nerve terminals. The typical vascular localization of autonomic neuropeptides is depicted in lower left (B), whereas the free nerve endings are typical localization of sensory neuropeptides (C). The immunoreactivity is seen in the paratenon and surrounding loose connective tissue, whereas the proper tendinous tissue, notably, is almost devoid of nerve fibers. Reprinted with permission from Ackermann et al.¹³ m, muscle; pt, paratendon; PGP 9.5, protein gene product 9.5.

Figure 3.

(A, B) Overview micrographs of longitudinal sections through the Achilles tendon at 2 weeks postinjury (rupture). Incubation with antisera to a nerve growth marker, GAP-43. Micrographs depict the proximal half of the Achilles tendon at increasing magnification. Arrows denote varicosities and nerve terminals. The GAP-positive fibers, indicating wound reinnervation, are abundantly observed in the healing proper tendon tissue. Reprinted with permission from Ackermann et al. GAP-43, growth associated protein 43.

Figure 4.

Area occupied by nerve fibers (%) immunoreactive to SP, CGRP, and GAL in relation to total healing area, over 16 weeks posttendon injury (mean±SEM). Reprinted with permission from Ackermann et al. CGRP, calcitonin gene-related peptide; GAL, galanin.

Figure 5.

Immunofluorescence micrograph of longitudinal sections through healing Achilles tendon at 1 (A) and 2 (B) weeks postrupture after incubation with antisera to CGRP. Nerve fibers immunoreactive to CGRP at week 1 are seen as vascular and free nerve endings in the loose connective tissue (A). At week 2, CGRP- immunoreactivity occurs mainly in the healing tendinous tissue as sprouting free nerve fibers (B). Scale bar=50 μm. Reprinted with permission from Ackermann et al. lct, loose connective tissue. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 6.

(A–C) Sirius red-polarized light micrographs of longitudinal sections through healing Achilles tendon at one postinjury of (A) substance P+captopril/thiorphan-, (B) captopril/thiorphan- and (C) saline-treated rats. Short green fibers denote collagen III-like structures. Scale bar=200 μm. Reprinted with permission from Carlsson et al. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 7.

(A, B) Immunofluorescence micrographs of longitudinal sections from biopsies of healthy Achilles tendon (A) and tendinosis tissue (B) after immunostaining for SP. Arrows denote varicosities and nerve terminals. The micrograph illustrates SP-positive nerve fibres in close vicinity to neoangiogenesis in the tendon proper (B). Scale bar=50 μm. Reprinted by permission from Lian et al. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/wound

Figure 8.

Relative expression of collagen I (A), collagen III (B), biglycan (C), versican (D), MMP-3 (E), and MMP-13 (F) mRNA in the intact and ruptured tendon of control (Wistar) and diabetic (GK) rats at day 14 postinjury. Results are expressed as means±SE with n=4 in Wistar groups and n=5 in diabetic GK groups. *p=0.05, **p=0.005 compared with intact Wistar and ^#p=0.05, ^##p=0.005 compared with intact GK group (single-factor analysis of variance). Reprinted by permission from Ahmed et al. GK, diabetic Goto-Kakizaki rats; MMP-3, matrix metalloproteinase 3.