Administration Methods of Mesenchymal Stem Cells in the Treatment of Burn Wounds
Abstract
:1. Introduction
2. Methods
2.1. Data Sources and Searches
2.2. Study Selection
3. Results
3.1. Study Characteristics
3.2. Clinical Studies
3.3. Preclinical Studies
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Inclusion Criteria | Exclusion Criteria |
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English language Original scientific studies In vivo studies Bone-marrow-, umbilical-cord-, or adipose-tissue-derived stem cells Cutaneous burn wounds | Not in English Review articles In vitro studies Radiation or chemical burn studies Other types of MSCs Non-MSC cells included in the treatment group Use of further differentiated MSCs Genetic alteration of MSCs beyond genetic marking |
Authors | Study Model | Patient Characteristics (n, Age, Sex, TBSA) | Burn Depth | Cell Species | Groups | Cell Delivery, Medium | Cell Dosage | Results (End Points) | |
---|---|---|---|---|---|---|---|---|---|
Dose (Passage) | Cells/ cm2 1 | ||||||||
Abo-Elkheir et al. (2017) [17] | Prospective case–control | n = 60, 18–35 y, male and female, 10–25% TBSA IC: Both sexes, age 15–50 y, TBSA 10–25% EC: Comorbidity, superficial or old burns, chemical, radiation or electric burns | Full thickness | Al BM-MSC, Al UC-MSC | Excision and STSG, excision and BM-MSC, excision and UC-MSC | Local injection, n/a | 1 × 105 cells/cm2 (n/a) | 1 × 105 | Increased rate of wound healing compared to STSG group, in both MSC groups, and shorter length of stay. Less early complications in BM-MSC group; infection was seen in 25% of the patients, but higher early complication rates in UC-MSC group; infection in 70%. Early complication rate was 50% in excision + STSG group. A total of 95% of patients in STSG group had late complications, compared to 45% in BM-MSC group and 30% in UC-MSC group. (Rate of burn healing, early and late complications, hospital stay length, costs) |
Jeschke et al. (2019) [18] | Case report | n = 1, male, mid-twenties, >70% TBSA 18 months after injury | Full thickness | Al UC-MSC and commercial Al Ch-MSC | Topical application and injection, fibrin sealant and Ringer’s lactate | 3 × 106 cells/mL in topical solution (n/a) | n/a | Rapid re-epithelialization. Reduction in wound percentage and healing of infections. Limited scarring over 6 years and no adverse effects. (Effect on burn wounds with delayed healing) | |
Mansilla et al. (2015) [19] | Case report | n = 1, 26 y, male 60% TBSA, 30% full thickness | Full thickness | Al cadaveric BM-MSC | n/a | Topical application, fibrinogen and thrombin spray | 1 × 104 cells/cm2 (P2) | 1 × 104 | Rapid epithelialization, more normal skin appearance compared to previous experiences in the burn unit. No adverse effects. (Safety) |
Rasulov et al. (2005) [20] | Case report | n = 1, 45 y, female 40% TBSA, 30% full thickness | Deep partial and full thickness | Al BM-MSC | n/a | Topical application, n/a | 2–3 × 104 cells/cm2 (n/a) | 2.5 × 104 | Rapid epithelialization. Increased angiogenesis and granulation. Pain relief. Good graft-take of STSGs. (Neo-angiogenesis and graft take) |
Wittig et al. (2020) [13] | Case series | n = 5, 2–58 y, male TBSA 12–55% IC: Age >= 2 y, full thickness burns, not healed within >= 21 days EC: Infection | Deep partial and full thickness | Al BM-MSC | n/a | Cell scaffold, pre-clotted PRP and thrombin | 1–3 × 107 cells per patient (n/a) | n/a | Early granulation tissue, rapid re-epithelialization. Full healing in 1–5 months. Recovery of pigmentation. Slight discoloration of healed skin, less hypertrophy, and contractures. (Effect on burn wounds with delayed healing) |
Authors | Animal Model (n) | Burn Depth | Cell Species | Administration Method, Medium | Cell Dosage | Results in MSC Group | |
---|---|---|---|---|---|---|---|
Dose (Passage) | Cells/cm2 1 | ||||||
A V et al. (2020) [21] | Rat (n/a) | Partial thickness | Xe BM-MSC, human | Cell scaffold and topical application (2 groups), hydrogel and DMEM | 1 × 106 cells (P3–5) | n/a | Increased wound contraction. Earlier wound closure, but only in scaffold group. No effect in topical MSC group. |
Abdel-Gawad et al. (2021) [22] | Rat (90) | Partial thickness | Al BM-MSC | Subcutaneous injection, DMEM | 2 × 106 cells/mL (n/a) | n/a | Increased wound healing. Reduced scar formation. |
Alapure et al. (2018) [23] | Mice (n/a) | Full thickness | Al BM-MSC | Cell scaffold, ACgel scaffold | 1 × 105 cells/scaffold (P3–5) | 5.1 × 105 | Increased wound closure rate, re-epithelialization, blood vessel growth and granulation. |
Caliari-Oliveira et al. (2016) [24] | Rat (134) | Full thickness | Xe BM-MSC, Mice | Intradermal injection, PBS | 5 × 106 cells/wound (P3–4) | 1.1 × 105 | Increased epithelialization after 60 days. |
Clover et al. (2015) [25] | Porcine (3) | Deep partial thickness | Al BM-MSC | Topical application, fibrin sealant (Tisseel™) | 4.5 × 106 cells/wound (P4) | 1 × 106 | Increased wound healing. Increased collagen density, increased epidermal area and dermal thickness. |
Fu et al. (2006) [26] | Porcine (6) | Deep partial thickness | Au BM-MSC | Local injection, n/a | 2 × 106 cells/wound (n/a) | n/a | Faster re-epithelialization, increased vascularization and collagen. |
Guo et al. (2016) [27] | Rat (49) | Deep partial thickness | Al BM-MSC | Cell scaffold, small intestinal submucosa | 5 × 105 cells/cm2 (P3) | 5 × 105 | Accelerated wound closure and granulation, vascularization and neo-epidermal cells. |
Ha et al. (2010) [28] | Rat (32) | Partial thickness | Al BM-MSC | Intradermal injection, saline solution | n/a (n/a) | n/a | Earlier wound closure. |
Hosni Ahmed et al. (2017) [29] | Rat (72) | n/a | Al BM-MSC | Local injection, PBS | 1 × 106 cells/mL (P3) | n/a | Accelerated wound healing. |
Imam et al. (2019) [30] | Rat (40) | Full thickness | Al BM-MSC | Local injection, PBS | 1 × 106 cells/cm2 (P3) | 1 × 106 | Increased wound healing and epithelialization. |
Imbarak et al. (2021) [31] | Rat (60) | Deep partial thickness | Al BM-MSC | Intradermal injection, PBS | 1 × 106 cells/wound (n/a) | n/a | Accelerated wound healing, increased epidermal thickness. Regenerated hair follicles. |
Liu et al. (2008) [32] | Porcine (24) | Deep partial thickness | Au BM-MSC | Cell scaffold, collagen-GAG | 2 × 106 cells/mL (P2–5) | n/a | Better healing and keratinization, less wound contraction. Increased vascularization. No adverse effects. |
Lykov et al. (2017) [33] | Rat (25) | Partial thickness | Al BM-MSC | Local injection, n/a | 2 × 105 cells/wound (P2–4) | n/a | Decrease in defect skin area, increased re-epithelialization and wound closure rate. |
Mansilla et al. (2010) [12] | Porcine (1) | Full thickness | Xe BM-MSC, rabbit | Topical application, fibrin sealant | 2 × 106 cells/mL/cm2 (n/a) | n/a | Increased granulation, vascularization, healing of wound with skin appendages. |
Mohajer Ansari et al. (2020) [34] | Rat (48) | Deep partial thickness | Al BM-MSC | Intradermal injection, PBS | 1 × 106 cells (n/a) | 4.4 × 105 | Increased biomechanical strength of wound, increased wound closure rate, increased epithelialization, increased remodeled collagen content, increased angiogenesis. |
Oh et al. (2018) [35] | Mice (30) | Full thickness | Al BM-MSC | Systemic injection, n/a | 5 × 105 cells/mouse (n/a) | n/a | MSC migration to burn wound and increased wound healing. |
Palakkara et al. (2020) [36] | Rat (105) | Full thickness | Al BM-MSC | Cell scaffold and local injection, Chitosan powder and decellularized porcine SIS (two groups) | 1 × 106 cells/wound (P3) | n/a | Increased angiogenesis and re-epithelialization. Best results in scaffold group. |
Paramasivam et al. (2021) [37] | Rat (75) | Full thickness | Al BM-MSC | Cell scaffold, acellular porcine bladder | 2.5 × 106 cells/scaffold (P3) | n/a | Increased rate of healing. Increased granulation and early angiogenesis. Increased and more regular collagen deposition. |
Rasulov et al. (2006) [38] | Rat (30) | Deep partial thickness | Al BM-MSC | Topical application, n/a | 2 × 104 cells/wound (n/a) | n/a | Increased angiogenesis and granulation. |
Revilla et al. (2016) [39] | Rat (12) | Full thickness | Al BM-MSC | Local injection, n/a | 2 × 106 cells/wound (n/a) | n/a | Faster wound healing, increased collagen type 1. No infection in MSC group. |
Revilla et al. (2018) [40] | Rat (10) | Full thickness | Al BM-MSC | Local injection, n/a | 2 × 106 cells/wound (n/a) | 8.9 × 105 | Accelerated wound closure, good healing quality. |
Revilla et al. (2020) [41] | Rat (30) | Full thickness | Xe BM-MSC, human | Subcutaneous injection, n/a | 2 × 106 cells/mL (n/a) | n/a | Accelerated wound healing, increased re-epithelialization. |
Rodriguez-Menocal et al. (2022) [42] | Porcine (4) | Full thickness | Al BM-MSC | Local injection, n/a | n/a (P1) | n/a | Reduced wound contraction, less collagen type I/III deposition. Reduced scarring. |
Sharifi et al. (2021) [43] | Rat (48) | Partial thickness | Al BM-MSC | Cell scaffold and local injection (3 groups), Aloe vera gel, chitosan-based gel and n/a | 2 × 106 cells/wound (n/a) | n/a | Earlier wound closure. Increased angiogenesis and granulation. |
Shumakov et al. (2003) [44] | Rat (40) | Full thickness | Au and Al BM-MSC | Topical application, n/a | 2 × 106 cells/wound (n/a) | n/a | Increased wound closure rate, most in Au group. Increased angiogenesis and granulation. |
Wu et al. (2021) [45] | Rat (n/a) | Deep partial thickness | Al BM-MSC | Intradermal injection, n/a | 1 × 106 cells/wound (P5–7) | n/a | Increased wound closure rate and healing. |
Xue et al. (2013) [46] | Mice (60) | Full thickness | Xe BM-MSC, human | Intradermal injection and topical application, PBS and growth factor reduced matrigel | 1 × 106 cells/wound (n/a) | n/a | Increased wound healing and angiogenesis. Faster wound closure. Found MSCs in other tissues than treated. |
Authors | Animal Model (n) | Burn Depth | Cell Species | Administration Method, Medium | Cell Dosage | Results in MSC Group | |
---|---|---|---|---|---|---|---|
Dose (Passage) | Cells/cm2 1 | ||||||
Alemzadeh et al. (2020) [47] | Rat (12) | Full thickness | Al ASC | Topical application and local injection around wound, hyaluronic acid hydrogel, covered with ADM | 1 × 106 cells/wound (P3–5) | 1.3 × 106 | Increased wound closure rate. Reduced inflammation, increased angiogenesis and granulation. |
Andrade et al. (2020) [48] | Rat (96) | Full thickness | Xe ASC | Intradermal injection, n/a | 1.5 × 106 cells/wound (P4–5) | 2.1 × 105 | Increased wound closure rate. |
Barrera et al. (2021) [49] | Mice (32) | Partial thickness | Al ASC | Cell scaffold and injection (2 groups), collagen–pullulan hydrogel and n/a | 2.5 × 105 cells/wound (P0–2) | n/a | Accelerated wound healing in scaffold group. Increased vascularization. |
Bliley et al. (2016) [50] | Mice (24) | Full thickness | Xe ASC, human | Subcutaneous injection, PBS | 6.8 × 106 cells/wound (P3) | n/a | No statistical difference in wound closure times. ASC enhanced vascularization, collagen deposition and adipocyte differentiation. Increased hair follicle regeneration. |
Boukani et al. (2022) [51] | Rat (36) | Full thickness | Al ASC | Cell scaffold, decellularized dOSIS | n/a (P3) | n/a | Increased wound closure rate, increased angiogenesis and collagen deposition. Multi-layer epidermis in MSC group. |
Burmeister et al. (2018) [52] | Porcine (6) | Deep partial thickness | Al ASC | Topical application, FPEG hydrogel (fibrin-based) | 1 × 105, 5 × 105 and 1 × 106 cells/wound, 3 groups (n/a) | 7.6 × 104 | Increased size of blood vessels and collagen deposition dose-related to ASC. |
Cabello-Arista et al. (2022) [53] | Mice (25) | Full thickness | Xe ASC, human | Cell scaffold, radiosterilized human amnion and pig skin | 6 × 104 cells/cm2 (n/a) | 6 × 104 | No effect on wound closure. Increased collagen deposition. |
Chen et al. (2017) [54] | Rat (15) | n/a | Al ASC | Subcutaneous injection, PBS | 1 × 106 cells/wound (n/a) | 1.4 × 105 | Accelerated wound healing rate. |
Chung et al. (2016) [55] | Rat (n/a) | Full thickness | Al ASC | Cell scaffold, PEGylated fibrin gel | 4 × 105 cells/gel (P3–5) | 7.6 × 104 | Earlier neovascularization. Better tissue organization. |
Costa de Oliveira Souza et al. (2021) [56] | Rat (70) | Deep partial thickness | Al ASC | Cell scaffold, nanostructured cellulose–gellan–xyloglucan–lysozyme dressing | 1 × 103 cells/cm2 (n/a) | 1 × 103 | Increased wound healing |
Dong et al. (2020) [57] | Mice (15) | Deep partial thickness | Al ASC | Topical application, conformable hydrogel | 3 × 105 cells/wound (P3–5) | n/a | Significantly increased healing rate and accelerated wound closure. Enhanced neovascularization, reduction in scar formation. |
Feng et al. (2019) [58] | Rat (12) | Deep partial thickness | Al ASC | Intradermal injection, PBS | 5 × 105 cells/wound (P3) | 5 × 105 | Increased healing at all time points, vascular density and percentage of live follicles. |
Franck et al. (2019) [59] | Rat (23) | Full thickness | Al ASC | Intradermal injection, n/a | 3.2 × 106 cells/wound (n/a) | 6.6 × 105 | Increased wound healing and collagen deposition. Decreased lymphatic vessels. No significant difference in vascular amt. |
Fujiwara et al. (2020) [60] | Ovine (7) | Full thickness | Al ASC | Topical application, PBS | 7 × 106 cells/wound (P4) | 2.8 × 105 | Improved graft-take and graft size. Increased blood flow and epithelialization. |
Gholipourmalekabadi et al. (2018) [61] | Mice (75) | Full thickness | Al ASC | Cell scaffold, decellularized human amniotic membrane | 1 × 104 cells/scaffold (P2) | 1.3 × 104 | Accelerated wound healing, reduced scarring, increased neo-vascularization and re-epithelialization. |
Karimi et al. (2014) [62] | Mice (40) | Full thickness | Al ASC | Local injection, n/a | 1 × 106 cells/mL (n/a) | n/a | Not statistically significant improvements. |
Karina et al. (2019) [63] | Rat (28) | Partial thickness | Xe ASC, human | Intradermal injection, saline | 4 × 105 cells (P1) | n/a | Increased wound closure rate, but delayed wound closure at end of study compared to the control. Increased re-epithelialization, larger and more prominent skin appendages, increased angiogenesis. |
Karina et al. (2021) [64] | Rat (30) | Deep partial thickness | Xe ASC, human | Intradermal injection, n/a | 4 × 105 cells/rat (P1) | n/a | Increased wound healing rate. Increased differentiation of healed skin. Increased vascularization. Not accelerated epithelialization. |
Loder et al. (2014) [65] | Mice (20) | Partial thickness | Al ASC | Subcutaneous injection, PBS | 1 × 106 cells/wound (P3+) | n/a | Decreased wound depth, decreased apoptosis, increase in vascularization (not significant). |
Lu et al. (2020) [66] | Rat (25) | Partial thickness | Xe ASC, human | Topical application, gelatin hydrogel and suspension | n/a (n/a) | n/a | Increased wound closure rate, most in group using hydrogel compared to cell suspension. Increased epidermal thickness. |
Motamed et al. (2017) [67] | Rat (32) | Full thickness | Xe ASC, human | Cell scaffold, human amniotic membrane | 5 × 105 cells/cm2 (P3) | 5 × 105 | Increased wound closure rate, lower inflammatory cell infiltration. Most healing in the first 14 days. |
Ng et al. (2021) [68] | Mice (42) | Full thickness | ASC, n/a | Topical application, gellan gum-collagen hydrogel | 6 × 104 cells/wound (P3–5) | n/a | Increased wound healing and closure rate. |
Oryan et al. (2019) [69] | Rat (48) | Full thickness | Al ASC | Intradermal injection and topical application, Aloe vera hydrogel | 1 × 106 cells/wound (P3–5) | 1.3 × 106 | Increased rate of healing, less inflammation. |
Oryan et al. (2019) [70] | Rat (48) | Full thickness | Al ASC | Intradermal injection and topical application, honey | 1 × 106 cells/wound(P3–5) | n/a | Increased angiogenesis, re-epithelialization and granulation. |
Roshangar et al. (2021) [71] | Rat (36) | Full thickness | Al ASC | Cell scaffold, 3D-printed collagen and alginate scaffold | n/a (n/a) | n/a | Accelerated wound contraction and healing. Increased re-epithelialization, and multi-layer epidermis. |
Shokrgozar et al. (2012) [72] | Rat (10) | Full thickness | Al ASC | Cell scaffold, collagen–chitosan | n/a (n/a) | n/a | Increased wound healing rate, increased epithelialization. |
Wu et al. (2021) [73] | Mice (32) | Full thickness | Al ASC | Cell scaffold, 3D GS alginate hydrogel | 2 × 106 cells/scaffold (P3–5) | 8.9 × 105 | Faster epithelialization. Increased angiogenesis and collagen deposition. |
Zhou et al. (2019) [74] | Rat (27) | Full thickness | Au ASC | Subcutaneous injection, n/a | 2 × 106 cells/wound P3) | 1 × 106 | Increased wound healing and angiogenesis. |
Authors | Animal Model (n) | Burn Depth | Cell Species | Administration Method, Medium | Cell Dosage | Results in MSC Group | |
---|---|---|---|---|---|---|---|
Dose (Passage) | Cells/cm2 1 | ||||||
Afzali et al. (2022) [75] | Rat (40) | Superficial partial thickness | Xe UC-MSC, human | Cell scaffold and local injection, PRP cryogel and cell culture medium (two groups) | 2 × 106 cells (n/a) | n/a | Improved wound healing, increased wound closure rate, best results in scaffold group. Increased re-epithelialization and increased early neo-angiogenesis. |
Cheng et al. (2020) [76] | Porcine (4) | Full thickness | Xe WJ-MSC, human | Topical application, in situ fibrin–HA bioink | 1 × 106 cells/mL (P1) | n/a | Better healing with less inflammation, scarring and contraction. Increased re-epithelialization, better archeology. No infection. |
Gholipour-Kanani et al. (2012) [77] | Rat (12) | Full thickness | Xe WJ-MSC, human | Cell scaffold, Cs:PVA nanofibrous web | 4 × 104 cells/scaffold (P1) | 1.8 × 104 | Accelerated wound healing and wound closure rate. Less inflammation. Increased re-epithelialization and granulation, regular pattern of regenerated collagen. |
Gholipour-Kanani et al. (2014) [78] | Rat (12) | Full thickness | Xe WJ-MSC, human | Cell scaffold, PCL:Cs:PVA nanofibrous web | 4 × 104 cells/scaffold (P1) | 4.2 × 104 | Accelerated healing process, but longer than non-burn wound group. Increased collagen deposition, granulation, and re-epithelialization. No complications reported. |
Hashemi et al. (2020) [79] | Rat (32) | Full thickness | Xe WJ-MSC, human | Cell scaffold, HAM | 1 × 106 cells/scaffold (P3) | n/a | Increased rate of healing, re-epithelialization, granulation. Mature and organized scar tissue, less hemorrhage and inflammation. |
Jehangir et al. (2022) [80] | Rat (35) | Partial thickness | Xe WJ-MSC, human | Cell scaffold, A-PCL composite scaffold and collagen (two groups) | 1 × 105 cells/cm (P1) | 1 × 105 | Increased wound healing and complete epithelialization in both MSC groups, best in A-PCL-WJ-MSC group with complete epidermal restoration and near normal skin appendage regeneration. Wound infection in one animal in the collagen-WJ-MSC group. |
Nazempour et al. (2020) [81] | Rat (40) | Full thickness | Xe WJ-MSC, human | Cell scaffold, ADM | 2 × 106 cells/scaffold (n/a) | n/a | Increased wound closure rate, angiogenesis, granulation, and epithelialization. |
Pourfath et al. (2018) [82] | Rat (24) | Full thickness | Xe WJ-MSC, human | Topical application, cell spray + sterile gauze Vaseline covering | 5 × 105 cells/wound (P3) | n/a | Increased re-epithelialization and granulation, decreased hemorrhage and inflammation. |
Zhang et al. (2015) [83] | Rat (84) | Full thickness | Xe WJ-MSC, human | Subcutaneous injection, saline | 2 × 106 cells/rat (P2–4) | n/a | Significantly higher wound healing rate, shorter wound healing time. Lower increase in inflammatory cytokines. |
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Jenssen, A.B.; Mohamed-Ahmed, S.; Kankuri, E.; Brekke, R.L.; Guttormsen, A.B.; Gjertsen, B.T.; Mustafa, K.; Almeland, S.K. Administration Methods of Mesenchymal Stem Cells in the Treatment of Burn Wounds. Eur. Burn J. 2022, 3, 493-516. https://doi.org/10.3390/ebj3040043
Jenssen AB, Mohamed-Ahmed S, Kankuri E, Brekke RL, Guttormsen AB, Gjertsen BT, Mustafa K, Almeland SK. Administration Methods of Mesenchymal Stem Cells in the Treatment of Burn Wounds. European Burn Journal. 2022; 3(4):493-516. https://doi.org/10.3390/ebj3040043
Chicago/Turabian StyleJenssen, Astrid Bjørke, Samih Mohamed-Ahmed, Esko Kankuri, Ragnvald Ljones Brekke, Anne Berit Guttormsen, Bjørn Tore Gjertsen, Kamal Mustafa, and Stian Kreken Almeland. 2022. "Administration Methods of Mesenchymal Stem Cells in the Treatment of Burn Wounds" European Burn Journal 3, no. 4: 493-516. https://doi.org/10.3390/ebj3040043