Wound pathophysiology and healing dynamics for stem cell-mediated therapeutics in different skin wounds

Table 1 Types of mechanical wounds and wound management[6,7]

Mechanical wounds	Overview	Wound management and concerns
Abrasions	Superficial damage to epidermis, may involve upper dermis	Rarely require sutures
Avulsions	Tearing away of the skin and underlying soft tissue. Irregular wound edges and flaps, exposing underlying structures. Prone to ischemia	Associated with a higher infection risk. Often require layered closure or delayed primary repair
Contusions	Blunt-force injuries damage skin and underlying tissue without necessarily breaking the epidermis	May evolve into hematomas or mask deeper injuries such as fractures or compartment syndrome
Lacerations	Linear or jagged tears in the skin caused by sharp or blunt trauma. Depth and location determine risk for nerve, tendon, or vascular involvement	Often present with well-defined edges commonly managed with primary closure
Puncture wounds	Caused by narrow, pointed objects that penetrate deep into tissue. External opening may be small, but underlying structures can be injured	Risk of infection is high, especially with contaminated or deep punctures
Bite injuries	Bites pose a significant infection risk due to oral flora from humans, dogs, or other animals	Human bites especially hands are considered at high-risk and require prophylactic antibiotics and delayed closure
Crush injuries	Prolonged pressure or force damages skin and underlying tissue. May cause compartment syndrome or rhabdomyolysis	Concerns are tissue viability, decompression, and infection
High-pressure injection injuries	Injuries from paint guns, air, solvents, gasoline, hydraulic fluid, grease, and water. Wound may appear minor, but damage can be severe	X-ray to check if a foreign body is suspended. Antibiotics for contaminated wounds, delayed presentation
Incision wounds	Cuts caused by sharp objects like glass, razor blades, and knives or as a result of surgery. The surface of the skin is where the cutting edge tangentially moves. Often, an incised wound is longer than it is deep	Prone to infection, prophylactic intraoperative incisional wound irrigation is required, in which debris, metabolic waste, and exudate are washed away just before wound closure

Table 2 Comparison of various preconditioning approaches

No.	Preconditioning strategy	Mechanism of action	Consideration
1	Hypoxic preconditioning	Low O2 stimulates hypoxia-inducible factor production, which in turn stimulates the expression of genes involved in cell survival, proliferation, migration, angiogenesis, metabolism, and cell apoptosis[77]. Preconditioned cells secrete extracellular vesicles that contain proteins, lipids, nucleic acids, and metabolites, and induce therapeutic effects through paracrine signaling[78]	Time duration and %O2 provided for hypoxia need to be optimized. Mainly essential for cell survival after transplantation
2	Compound/small molecule preconditioning	Compounds or small molecules may possess immunomodulatory, anti-inflammatory, and antioxidant properties. They may induce cell proliferation and differentiation[72,73,78]	Cytotoxicity profile and effective dose optimization need to be done. Utilized when considering a specialized aspect or stem cell differentiation towards a specific lineage
3	Genetic engineering of MSCs	Genetic or epigenetic modification of MSCs is done to modify the expression of various genes involved in cell proliferation, differentiation or other immunomodulatory properties[74-76]	For specialized therapeutic aspects or stem cell differentiation towards a specific lineage. It involves genetic manipulation

Table 3 Ongoing and completed clinical trials using mesenchymal stem cells for wound healing and related disorders

Wound/injury	Site of transplantation/implantation	Additional agents	Autologous/allogeneic	Cell source	Phase	NCT number
Mandible fractures	Local application on the fracture site during the surgical procedure	-	Autologous	Adipose tissue	3	02755922
Tibial closed diaphyseal fractures	Local application in the fractured site	-	Allogeneic	Adipose tissue	2	02140528
Tendon injury	Ultrasound-guided injection at the injury site	-	Allogeneic	Adipose tissue	1	01856140
Non union fracture	Local application	Biphasic calcium phosphate biomaterial granules and iliac crest graft	Autologous	Bone marrow	3	03325504
Second- or third-degree burns	Local application	Plasma fibrin hydrogel	Allogeneic	Adipose tissue	2	03113747
Heel injury	Local application	Skin graft	Allogeneic	Umbilical cord	1	04219657
Poor healing after uterus injury	Intrauterine injection	-	Allogeneic	Umbilical cord	1	03386708
Second degree burn wounds of less than 20% of the total body surface area	Local application	-	Allogeneic	N/A	1	02104713
Chronic wounds in diabetic foot syndrome	Direct application onto the prepared wound bed	Fibrin gel	Allogeneic	Adipose tissue	1-2	03865394
Non-union of long bone fractures	Local application in fractured zone	-	Autologous	Bone marrow	1	01206179
Non-united tibial and femoral fractures	Injection in non-union site	-	N/A	Bone marrow	2	01788059
Tendon injury	Local injection under ultrasound guidance	Fibrin glue + range of motion exercise	Allogeneic	Adipose tissue	2	02298023
Distal tibial fractures	Local implantation at the fracture site	MSC carrier	Autologous	N/A	1-2	00250302
Ocular corneal burn	Subconjunctival injection	-	N/A	Bone marrow	2	02325843
Fracture non-union healing	Local application of in vitro-expanded MSC	Carrier	Autologous	Bone marrow	N/A	02177565
Chronic ulcer wounds	Topical application of Wharton jelly MSC culture medium	Gel carrier	Allogeneic	Umbilical cord	1	04134676
Knee articular cartilage injury	Local application	-	Allogeneic	Umbilical cord	3	01041001
Deep second-degree burn wound	Local application	Hydrogel sheet	Allogeneic	Adipose tissue	1	02394873
Long bones non-union	Percutaneous application around fracture ends	-	Autologous	Adipose tissue	1-2	04340284
Knee articular cartilage injury or defect	Local application	-	Allogeneic	Umbilical cord	3	01626677
Support of autologous chondrocyte transplantation with instant MSCs	Filling of cartilage defect	Glue carrier, autologous chondrons	Allogeneic	N/A	1-2	02037204
Tibial shaft fracture	Local injection	-	Autologous	Bone marrow	N/A	00512434
Mandibular distraction osteogenesis	Local injection	-	N/A	Bone marrow	N/A	03861650
Severe epidermolysis bullosa	Serial infusions	Allogeneic hematopoietic stem cell transplant	Allogeneic (related)	N/A	2	02582775
Severe epidermolysis bullosa	Infusions	Allogeneic hematopoietic stem cell transplant	Allogeneic	N/A	1-2	01033552
Recessive dystrophic epidermolysis bullosa	Infusions	-	Allogeneic	Umbilical cord blood	1-2	04520022
Epidermolysis bullosa	Local application	Hydrogel sheet	Allogeneic	Adipose tissue	1-2	02579369
Epidermolysis bullosa	Local application	Hydrogel sheet	Allogeneic	Adipose tissue	1-2	03183934
Treatment-refractory chronic venous ulcers	Topical application	-	Allogeneic	Skin derived	1-2	03257098
Recessive dystrophic epidermolysis bullosa	Infusions	-	Allogeneic	Skin derived	1-2A	03529877

NCT: National clinical trial; N/A: Not applicable; MSCs: Mesenchymal stem cells.