๐ ็ธฝ็ฎ้ ๏ฝ ๐ ่ฑๆๅๆ๏ผๆฌ็ฏ๏ผ ๏ฝ ๐ ๅฎๆด็ฟป่ญฏ ๏ฝ โญ ็ฒพ่ฏ็ญ่จ
FUTURE DIRECTIONS
Currently limitations in the treatment of chronic wounds are partly due to an incomplete understanding of the molecular mechanisms hindering repair and a lack of animal models that reflect the complex multifactorial nature of chronic ulcers. In addition, clinical research is often hampered by a heterogeneous patient population with a range of comorbidities. The success of innovative therapies will depend on comprehensive knowledge of the underlying pathomechanisms and correction of pathogenic factors, with advances in molecular diagnostics and material sciences playing a key role.
Stem Cells
Recent advances in stem cell biology may provide novel treatment strategies for acute and chronic wounds (Fig. 141.10). There is great interest in delivering stem or progenitor cells, either applied topically or via stimulation of their recruitment from the circulation into the wound site. Preliminary work suggests that topically applied autologous bone marrow-derived cells promote the healing of treatment-resistant chronic wounds. Furthermore, recruitment of CD34+ cells from the circulation has shown promise in ischemic limbs. Adipose tissue also serves as a reliable source of mesenchymal stromal/stem cells. Lastly, advances in induced pluripotent stem cell (iPSC) technology and gene editing of somatic cells hold great promise for improving the skinโs regenerative capacity. However, stem cell therapy still poses many questions regarding potential side effects and stem cell survival and differentiation within the hostile โchronic woundโ environment.
Molecular Modeling of Growth Factors
Advances in biomaterial science and protein engineering are expected to contribute to the development of novel therapies for tissue repair. For example, the creation of protease-resistant growth factors might circumvent the imbalance in proteolytic activity that is characteristic of chronic wounds. When growth factors were engineered to have enhanced binding to ECM molecules, they demonstrated augmented biologic properties associated with tissue repair. This approach not only utilizes the ECM as a carrier, but it also mimics the natural interactions between growth factors and the ECM, which appears to be crucial for the physiologic actions of growth factors.
Biomaterials and Tissue Engineering
Currently, collagen- or fibrin-based products are the most commonly employed biomaterials for guiding tissue regeneration. They are used as carriers for transplanted cells, as acellular scaffolds, or as an immediate coverage for large trauma- or disease-associated skin defects. However, their mechanisms of healing action remain speculative and well-controlled clinical trials are needed.
Preclinical studies of various synthetic materials are underway in which three-dimensional extracellular microenvironments are being used to mimic natural extracellular matrices. For example, bioactive components, including heparin, cyclic Arg-Gly-Asp (RGD) adhesion peptides, and growth factors, have been integrated into polyethylene glycol (PEG)-based hydrogel matrices. Clinical studies will need to establish the physiologic relevance of these synthetic materials and their ability to encourage new tissue growth within wounds.
Wound Metabolism
Wound healing represents a metabolically demanding process and during the healing response cells have to adapt to their different metabolic requirements. In general, the resulting metabolites are regarded as waste products and cellular metabolism is viewed as necessary for controlling energy homeostasis. However, there is emerging evidence that metabolites have critical signaling functions and cellular metabolism is tightly linked to the orchestration of cell activation and function. Enhanced understanding of how cell-intrinsic and -extrinsic metabolic changes are linked to wound healing will be important in the future as this could lead to the development of new diagnostic and therapeutic approaches that enforce endogenous repair mechanisms and normalize pathologic healing conditions.
Wounding stimulates the engraftment of bone marrow-derived stem/progenitor cells to the skin and induces bone marrowderived cells to incorporate into skin structures. Therefore, bone marrow might provide a valuable source of stem cells for skin repair. Furthermore, differentiated cells can be isolated from skin biopsies, propagated and/or genetically modified in vitro, and either applied directly to the wound bed or combined with biologic/synthetic biomaterials to be applied as composite skin graft.
Advances in Systemic Drug Development
Chronic wounds and excessive tissue fibrosis are often symptoms of an underlying systemic disorder (e.g. vasculitis, pyoderma gangrenosum) or predisposing condition (e.g. older age). Over the past decade, there have been significant drug developments as well as an escalation in drug repurposing of immunomodulators (e.g. biologics, small molecules) and anti-aging medications (e.g. metformin, mTOR inhibitors). In other words, the efficacy of drugs that target a single cytokine or signaling pathway in several different organs (e.g. joints, gut, skin) has stimulated a shift from organ-based to molecular-based disease concepts. Importantly, impaired cutaneous wound healing
Fig. 141.10 Stimulation of tissue regeneration via cell therapy.
associated with inflammatory systemic disorders (e.g. vasculitic ulcers in rheumatoid arthritis, pyoderma gangrenosum) has been found to improve with cytokine-specific therapeutic strategies. It is therefore likely that in the future patients with impaired wound healing will indirectly benefit from advances in drug development where the intended disease indications did not include enhanced wound healing.
Additional figures and tables on Chemical mediators of inflammation that play a role in wound healing and Different types of matrix metalloproteinases involved in wound repair, available in our eBook (see inside front cover for access code).