1. Introduction
Skin wounds activate repair mechanisms to restore tissue structure and function [ 1 , 2 ]. However, chronic wounds often stall in a pro-inflammatory M1 macrophage state, failing to transition toward a regenerative M2 phenotype [ 3 ]. Current consensus through the TIMERS framework (Tissue, Infection/Inflammation, Moisture, Edge, Repair/Regeneration, Social factors) emphasizes that social factors—including the patient’s will to avoid invasive surgery—are critical to healing outcomes [ 4 ]. If a wound fails to heal significantly within four weeks, alternative non-intrusive strategies must be prioritized to reduce unnecessary intrusive practices.
To address the clinical and economic challenges of complex wounds, human amniotic membrane (hAM) offers a bioinductive matrix with antibacterial and anti-inflammatory properties [ 5 , 6 ]. hAM is utilized in ophthalmology to manage corneal perforations and neurotrophic keratopathy by providing an anti-inflammatory, prohealing substrate [ 7 , 8 ]. In oral and maxillofacial surgery, hAM has been used for repair of oral mucosal defects, vestibuloplasty, fistula closure, and management of medication-related osteonecrosis of the jaw, highlighting its versatility as a regenerative biomaterial [ 9 , 10 ]. In vascular surgery, decellularized hAM is fabricated into multilayered tubular grafts that outperform synthetics by promoting endothelialization and maintaining long-term patency [ 11 ]. These applications, alongside its use in regenerative medicine as a scaffold for cartilage repair, leverage the membrane’s natural extracellular matrix to facilitate tissue-specific integration [ 12 ]. In this study, we employed hAM-pe, a homogenized, lyophilized and gamma-sterilized preparation designed for the gradual release of biological factors and ease of clinical application, which has already been tested in 16 DFU patients without reported adverse effects [ 13 ].
This study was motivated by a patient-centered need: an adult male with an extensive gluteal ulcer who declined surgical grafting. Consequently, we describe a comparative evaluation of this non-invasive hAM-pe dressing against a commercial bovine collagen matrix (BCM), analyzing the local histological and molecular responses in a patient seeking to avoid surgical intervention.
2. Results
In this individual case, two distinct regions of the same ulcer were treated using different biomaterials: a bovine collagen matrix (BCM) and a lyophilized, homogenized human amniotic membrane dressing (hAM-pe) ( Figure 1 B). Both treatments were initiated on day 0 in separate wound regions. The BCM dressing was applied once on day 0 and secured with sutures, and after 15 days, the silicone layer was removed ( Figure 1 C). In contrast, hAM-pe was reapplied every 72 h from day 0 to day 49. The treated areas were followed until day 49. Although both matrices are routinely used for wound bed preparation prior to skin grafting and are expected to promote natural re-epithelialization [ 14 ], the hAM-pe-treated area showed a more favorable clinical appearance by day 49, including a broader re-epithelialized margin, less edema, and no visible fibrin-like exudate. Based on the more favorable evolution of the hAM-pe-treated area and the patient’s continued refusal of surgery, hAM-pe treatment was subsequently extended to the remaining wound surface from day 49 onward and continued until complete re-epithelialization was achieved approximately five months after treatment initiation ( Figure 1 F–H). After 49 days of treatment, under BCM treatment, prominent, irregular granulations were observed, with whitish secretion consistent with fibrin deposits ( Figure 1 , ψ) and signs of edema ( Figure 1 , ε). In contrast, the portion treated with hAM-pe exhibited a wider re-epithelialized edge evidenced by a glossy surface ( Figure 1 , *), suggesting the presence of an incipient keratin layer. Compared with the BCM-treated region, the hAM-pe-treated area showed less visible exudate and edema, which reflects the reduced local inflammatory activity.
Additionally, a histological evaluation was performed on biopsies from the zones treated with BCM and hAM-pe, taken at equivalent distances from the initial wound margin ( Figure 1 , panel G, double-arrowed lines).
In the zone treated with hAM-pe, a tongue of re-epithelialization was observed, which was not apparent in the biopsy from the BCM-treated zone ( Figure 2 ). These histological findings suggest a more advanced re-epithelialization process following hAM-pe treatment. In addition, a structure composed of immune cells, including epithelioid cells and multinucleated giant cells, characteristic of a foreign-body-type granulomatous reaction was observed and confirmed by CD68 immunohistochemical staining ( Appendix A , Figure A1 ), between 250 and 400 µm in depth, in the zone treated with BCM. This type of structure, which represents a host response aimed at isolating the material and limiting damage to the surrounding tissue, was not observed in the zone treated with hAM-pe. Histological examination revealed that the dermal ECM under BCM treatment appeared disorganized with diffuse unstained white areas indicative of unstructured, edematous connective tissue. In contrast, the area under hAM-pe treatment, both beneath the re-epithelialization tongue and in the surrounding tissue, exhibited homogeneous staining without evidence of extravascular erythrocytosis.
To assess the composition and spatial arrangement of collagen fibers, biopsy samples were stained with Picrosirius red ( Figure 3 ). The ratio between type I and type III collagen fibers provides insight into whether the tissue has a normal composition or presents alterations [ 15 , 16 ]. Day 0 biopsies confirmed that no initial differences existed between the regions assigned to each treatment ( Appendix B , Figure A2 ). Assuming that the healing process occurs from the deepest layers of the ulcer toward the surface, the most recently synthesized tissue would be that closest to the surface, where treatments were applied. No differences were observed in the superficial provisional matrix: equal collagen type I/III ratios under both treatments, with an abundance of type III collagen, a hallmark of granulation tissue itself, were observed. However, at a depth of 0.5–1.5 mm, the hAM-pe-treated zone exhibited a higher collagen I/III ratio, indicative of ECM maturation. Accordingly, in the newly synthesized tissue layer over the ulcer bed where BCM was applied, the collagen deposition appeared focal and irregularly organized, particularly in areas suggestive of a foreign-body-type granulomatous reaction at a depth of 1500 to 3000 µm ( Figure 3 , panel C, arrows). In contrast, hAM-pe dressings were associated with a more fibrillar-like collagen organization, appearing as parallel red/yellow lines in Figure 3 , panel B (dashed line). Finally, the comparison between the deepest regions of each biopsy holding the tissue beneath the original bed ulcer is useful to evaluate pre-existing-tissue maturation under the effects of each treatment. Whole-section scanning of this region also showed a higher collagen I/III ratio under hAM-pe treatment, suggesting an advanced progression of a remodeling process.
Given that many of the aforementioned estimates rely on Picrosirius red staining to differentiate collagen fiber types, and acknowledging the reported limitations of this method [ 17 ], we further investigated these hypotheses by analyzing molecular marker expression changes. The results of these analyses are presented in the following sections.
In order to analyze the vascularization state of the new tissue in the wound under both treatments, the cell surface marker CD34 was analyzed on biopsy sections. CD34 is a robust and functional marker of vascularization because its detection reflects the presence and activity of key cells involved in vascular formation and remodeling [ 18 ]. No differences were identified in the number of vessels present in the superficial region of the two initial biopsies ( Figure 4 C, day 0), nor were differences observed in vessel caliber ( Appendix C , Figure A3 ). Both observations support an equivalent vascularization between the areas set to receive the two treatments. After 49 days of treatment, images were significantly different under each treatment ( Figure 4 A,B). The zone treated with hAM-pe exhibited an increased count of CD34-positive circular structures indicative of blood vessels ( Figure 4 C, day 49). Additionally, a larger vessel diameter was observed in the same zone, as revealed by the microvascular sections of all detected structures examined at higher magnification ( Figure 4 D). These findings indicate that hAM-pe treatment significantly enhanced both the number and caliber of newly formed blood vessels over time compared to BCM treatment. When these processes are impaired, they can lead to edema and inadequate tissue oxygenation, ultimately compromising the healing process [ 19 ].
The clinical and histological observations described above suggested distinct local tissue responses under the two treatment conditions. To further characterize these findings, the expression of selected molecular markers was also analyzed, as described in Section 4 and represented in Figure 5 and Table 1 .
Regarding inflammation markers, hAM-pe treatment resulted in lower expression of TNF-α (ΔLFC = −1.77) and IL-1β (ΔLFC = −4.54) compared to BCM. Conversely, Arginase 1 expression was higher under hAM-pe (ΔLFC= 3.33), while no significant differences were observed for TGF-β. This profile suggests a modulation toward a regenerative state under hAM-pe [ 3 , 20 , 21 ]. Chemotaxis and vascularization markers also exhibited differential expression. Under hAM-pe, VEGF expression was higher (ΔLFC = 2.13) [ 22 , 23 ], whereas chemotactic markers CXCL-10, IL-8, and CCL-2 showed lower expression levels relative to BCM (ΔLFC < −2.30). These findings indicate reduced recruitment of inflammatory cells and sustained angiogenic signaling in the hAM-pe-treated area [ 24 ]. Regarding ECM deposition and remodeling, hAM-pe showed higher COL1A1 expression (ΔLFC = 0.90), while no significant differences were detected for COL3A1 or α-SMA. Enzymatic markers associated with matrix turnover, including Gelatinase MMP-2 (ΔLFC = −1.26), protease inhibitor TIMP-1 (ΔLFC = −1.18), and serine-protease FAP (ΔLFC = −1.95) [ 25 , 26 ], were lower under hAM-pe compared to BCM treatment. While MMP-1 was initially undetectable, its induction was observed in both treatments by day 49, being 10-fold higher in the hAM-pe-treated zone. These findings suggest that in the hAM-pe-treated area, the replacement of type III collagen with a more mature type I collagen matrix is already underway, whereas the BCM zone remains in an earlier stage of enzymatic remodeling [ 27 ].
3. Discussion
In this single-case intra-patient comparative study, hAM-pe was associated with the resolution of persistent inflammation and promotion of angiogenic features, as reflected by M2-like profiling and increased vascularization (VEGF/CD34+) [ 22 , 28 ]. In contrast, the BCM-treated area showed persistent pro-inflammatory features and foreign-body reactions, while the hAM-pe-treated region exhibited findings consistent with more advanced remodeling, including a higher collagen I/III ratio [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ].
Unlike conventional dermal substitutes that often require subsequent split-thickness skin grafting, the hAM-pe treatment used for this patient was associated with a non-surgical healing trajectory, facilitating spontaneous epithelialization from wound edges and adnexal structures. By avoiding the need for sutures or operating room intervention, this approach aligned with the patient’s preference to avoid surgery and was accompanied by a successful home-based recovery with improved quality of life.
Although these findings derive from a single-case report and cannot be generalized to the broader population, they suggest the potential of hAM-pe as a regenerative alternative deserving of further investigation. Larger controlled studies are required to determine its efficacy, safety, and reproducibility in complex wound management.
4. Materials and Methods
4.1. Patient and Skin Samples
This study was approved by the Ethics Committee of Research of the Hospital El Cruce, Argentina. The patient agreed to participate in this study, as well as to have its results published, and written informed consent was obtained from him. This study was developed in compliance with the regulations concerning current legal aspects in the Argentine Republic, adhered to requirements regarding respect for patients’ rights, and did not violate any national or international ethical guidelines, as reflected in the approval by the institution’s Human Research Review Committee.
An adult male patient with a 60 cm 2 gluteal ulcer (post-injection fasciitis, 1-month VAC) was referred while undergoing chemotherapy for multiple myeloma. To defer surgery per patient request, a comparative treatment was applied to two ulcer regions: commercial BCM vs. hAM-pe. The BCM was sutured and its silicone layer removed on day 15. while hAM-pe was applied every 72 h. For histological and molecular analysis, 0.5 cm punch biopsies were collected on days 0 and 49. Clinical progress was documented via photography.
4.2. Treatments
The BCM employed is a commercial product described as a three-dimensional porous bi-layer sterile matrix consisting of type I, purified, stabilized, freeze-dried bovine collagen and a polyester-reinforced silicone layer acting as a pseudo-epidermis [ 36 ].
hAM-pe dressingsare obtained by homogenizing, lyophilizing and sterilizing human amniotic membranes for which extensive donor screening is performed to ensure donor suitability. Material is obtained from the placenta after cesarean delivery, following informed consent. Together with placentas, a blood sample from the mother is provided and assessed for HIV, HBV, HCV, CMV, HTLV, Treponema pallidum , Brucella spp., Trypanosoma cruzi, and Toxoplasma gondii. Placentas are stored at 4 °C in sterile saline and transported to the AMNIOS BMA Tissue Bank, San Martín, Argentina. Primary processing is done within 24 h of the cesarean and involves manually separating the AM from the placenta under a class 100 biological safety cabinet. The hAM is homogenized with a handheld homogenizer and transferred to circular molds of 5.5 and 6.0 cm diameter for the lyophilization process using a BK-FD 10P lyophilizer. Then, the hAM-pe is packed inside 2 bags under a class 100 biological safety cabinet. After that, hAM-pe is sterilized through gamma radiation. The dressings are provided in circular shapes of 5.5 and 6.0 cm in diameter and 1.2 ± 0.1 mm in thickness. All processes are carried out following Good Manufacturing Practices approved by the National Administration of Drugs, Foods and Medical Technology (ANMAT, Ciudad Autónoma de Buenos Aires, Argentina) and AMNIOS BMA Tissue Bank, approved by the National Institute for Ablation and Implant (INCUCAI, Ciudad Autónoma de Buenos Aires, Argentina). Furthermore, control samples are sent to the microbiology service to determine the bioburden and to ensure sterilization has been achieved with the range of gamma radiation employed (15–25 kGy). hAM-pe remains in quarantine until all controls are completed. If stored at room temperature and away from direct light, hAM-pe has a shelf life of 3 years [ 13 ].
4.3. Histological Analysis
Four FFPE skin biopsies (5 µm) were blindly analyzed using H&E and Picrosirius red staining [ 37 ]. Polarized microscopy and ImageJ (Version: 2.14.0/1.54f) thresholding quantified collagen I/III ratios. IHC for CD34 (1:50) and CD68 (1:100) utilized HRP/DAB detection. Vessel density and diameter within the superficial 200 µm were quantified via the “Hot Spot” morphometric technique on CD34+ structures across selected ROIs [ 38 ].
4.4. Molecular Biology Analysis
Four biopsies were homogenized for RNA extraction (Tiangen, Beijing, China) and triplicate reverse transcription (iScript, Bio-Rad, Hercules, CA, USA). Relative gene expression (Actin-normalized) was analyzed via qPCR (iQ Bio-Rad, CFX96) using a 40-cycle protocol and melting curve verification. Primer sequences are shown in Table 2 . Relative mRNA expression was calculated via the −ΔΔCt method which provides a symmetric Log2 scale for up- and downregulation. Given N = 1, significance was defined by technical robustness: effects were significant if they exceeded three times the technical standard deviation, ensuring a 99% confidence interval against experimental noise.
5. Conclusions
In this single-patient case, treatment with hAM-pe was associated with more favorable clinical, histological, and molecular features compared with BCM, including resolution of local inflammation and findings consistent with more advanced tissue remodeling. The observed non-surgical healing trajectory and good tolerability highlight the potential of hAM-pe as a supportive approach in complex wound management. However, these findings are limited to intra-patient observation and cannot be generalized. Further controlled studies are required to evaluate the efficacy, safety, and reproducibility of this strategy.
Acknowledgments
Special thanks to Olga Andrea Santelices Iglesias and Carolina Natalia Zanuzzi from IMPA, Facultad de Ciencias Veterinarias, UNLP, Argentina, for their contribution to the histopathological processing and analysis.
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Author Contributions
Conceived and designed the analysis: M.X.G., A.B., G.N.M. and F.M.M. Collected the data: M.X.G., J.M.d.P.R., M.F.R. and R.A.C. Contributed data or analysis tools: M.X.G., J.M.d.P.R., E.V. and E.L.P. Performed the analysis: M.X.G. Wrote the paper and other contributions: M.X.G., M.F.R., R.A.C., A.B., G.N.M. and F.M.M. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Ethical review and approval were waived for this study due to it reporting on a single patient, with an official waiver issued by the Research Ethics Committee of Hospital de Alta Complejidad en Red El Cruce (date: 12 September 2024).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient to publish this paper.
Data Availability Statement
The data presented in this study are available in the article. Further inquiries can be directed to the corresponding author.
Conflicts of Interest
The authors declare no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript: α-SMA Alpha-Smooth Muscle Actin BCM Bovine Collagen Matrix CCL-2 Motif Chemokine Ligand 2 (Monocyte Chemoattractant Protein-1, MCP-1) CD34 Cluster of Differentiation 34 (marker of hematopoietic and endothelial progenitor cells) COL1A1 Collagen Type I Alpha 1 Chain COL3A1 Collagen Type III Alpha 1 Chain Ct Threshold Cycles CXCL-10 C-X-C Motif Chemokine Ligand 10 (Interferon gamma-induced protein 10) DFU Diabetic Foot Ulcer ECM Extracellular Matrix FAP Fibroblast Activation Protein hAM Human Amniotic Membrane hAM-pe Lyophilized Homogenized Human Amniotic Membrane Dressings Sterilized by Gamma Radiation HIV Human Immunodeficiency Virus IL-1β Interleukin 1 Beta IL-8 Interleukin 8 MMP-1 Matrix Metalloproteinase-1 MMP-2 Matrix Metalloproteinase-2 RNA Ribonucleic Acid ROI Region of Interest qPCR Quantitative Polymerase Chain Reaction TGF-β Transforming Growth Factor Beta TIMP-1 Tissue Inhibitor of Metalloproteinases-1 TNF-α Tumor Necrosis Factor Alpha VAC Vacuum-Assisted Closure VEGF Vascular Endothelial Growth Factor
Appendix A
Appendix B
Appendix C
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