Abstract
Context
Relapse and recurrence rates of pressure injuries (PIs) are very high in spinal cord injured patients. That is the reason why alternative therapies, such the stem cells derived from bone marrow, have been developed.
Objective
To compare this new technique of infiltration-infusion of mononuclear cells from bone marrow with conventional surgery.
Design
A retrospective study was carried out in patients with spinal cord injuries who had PIs, category III/IV, in the pelvic area, during a 14-year follow-up period.
Setting
One group was treated with conventional surgery and, in the other group, mononuclear cells were infused.
Participants
One hundred and forty-nine patients were registered, 63 (42.3%) in the conventional surgery group and 86 (57.7%) in the mononuclear cell group.
Results
A comparative study between these 2 groups was carried out. There were no significant differences in ulcer healing in the first 6 months, but 6 months and one-year post-treatment, they were found. At 6 months, no patient in the conventional surgery group showed dehiscence or fistulization of the wound and, one year after surgery, only 3.17% recurred in the conventional group. In addition, there was a statistically significant relationship between days of hospitalization and the type of bacterial contamination and the intervention group.
Conclusion
Bone marrow mononuclear cell infusion-infiltration is an alternative treatment for PIs and fistula during the first 6 months, instead of conventional surgery. However, in the medium-long term, conventional surgery is more effective.
KEYWORDS: Pressure injuries, Spinal cord injury, Mononuclear cells, Stem cell therapy
Introduction
Pressure injuries (PIs) (Fig. 1) are the skin injured areas of persistent hyperemia, with blisters or necrosis, which can progress and reach deeper structures, such as muscle and bone.1 They usually appear over bony prominences as a result of different mechanisms, such as ischemia, pressure, or pressure combined with shear.2 Zakrasek et al. tried to determine the prevalence of PIs in spinal cord injured patients in the developing world and concluded that there are currently little data on the prevalence or cost of PIs.3,4 Despite the inconsistency of the results collected, it is known that the prevalence of PIs in patients with spinal cord injuries has decreased in the last decades.5 The treatment of PIs is still a real therapeutic challenge, and traditionally consists in reducing pressure on damaged areas and debridement of all necrotic tissues, especially in stages III and IV, to ensure right evolution, reducing the risk of infection, and making the healing process easier.6
Figure 1.
Ischial pressure injury.
Many of the spinal cord injured patients are not candidates for surgical treatment and relapse and the recurrence rates are very high, even after adequate treatments.7 This has led to the development of a wide range of dressings adapted to the type of ulcer,8 promoted the use of electric-powered negative-pressure wound therapies8 and, also, the application of different mesenchymal stem cells as new treatment alternatives.9 Among them, the stem cells derived from the bone marrow have shown good results in the treatment of other pathologies like acute myocardial infarction10 or chronic ischemic wounds.11 Experimental studies on animals first and then its use in clinical practice, have shown that the transplantation of these mononuclear cells from the bone marrow promotes neovascularization in ischemic tissues and brings about the recruitment, through paracrine factors, of macrophages and endothelial cells resulting in wound healing.12 In addition, they stimulate the secretion of different factors, such as vascular endothelial growth factors or fibroblast growth factors, which prevent apoptosis, promote angiogenesis, contribute to the reorganization of the extracellular matrix and favor the recruitment of circulating cells.12,13
As far as we know, there are no studies that compare the benefits of cell therapy with benefits of conventional surgery. Consequently, the objective of this study was to compare the conventional treatment of PIs (control group) with the mononuclear stem cells derived from the bone marrow (experimental group) to determine if this novel approach gives a better outcome in the healing of these ischemic lesions.
Methods
Sample description
Cell therapy in PIs has been used in our hospital since the end of 2007. After more than ten years of obtaining good results, we decided to compare this technique with conventional surgery. A retrospective study was carried out in patients with spinal cord injuries who had a diagnosis of PIs, category III/IV, in the pelvic area, during a 14-year follow-up period, from 2000 to 2014. Retrospectively, we selected patients who were admitted to the Spinal Cord Injury Unit of the Central University Hospital of Asturias (HUCA), either from the ulcer itself or from other concomitant complications. The study started on 1st January 2000 and ended on 14th June 2014, when the hospital was moved to the current site, because data collected prior to the transfer were more accurate. We decided to review cases from previous years to the introduction of cell therapy to have a large and representative sample, especially with the conventional surgery group, because from 2007 to 2014 most of patients with PIs received cell therapy. Therefore, we made two different groups: patients treated with cell therapy and patients treated with conventional surgery. The first group included patients treated with the bone marrow-derived mononuclear cells from 2007 to 2014 and, the second group included patients treated with conventional surgery from 2000 to 2014, to obtain a sufficient sample. All patient demographics are summarized in Table 1.
Table 1.
Patients’ demographics.
| Patient data | Number (%) |
|---|---|
| Age (mean, standard deviation, range) | 52.15 (12.42, 20–80) |
| Female | 52.55 (14.25, 32–75) |
| Male | 52.09 (12.13, 20–80) |
| Sex | |
| Male | 128 (85.9) |
| Female | 21 (14.1) |
| Mean hospital stay | 64.09 days (36.05; 28.04–100.14) |
| Type of spinal cord injury | |
| Paraplegic | 120 (80.5) |
| Tetraplegic | 29 (19.5) |
| Ulcer location | |
| Ischial | 104 (69.8) |
| Sacral | 26 (17.4) |
| Trochanteric | 19 (12.8) |
| Ulcer laterality | |
| Right | 65 (43.6) |
| Left | 58 (39.0) |
| Midline | 26 (17.4) |
| Year of intervention | |
| 2000 | 2 (1.34) |
| 2001 | 5 (3.36) |
| 2002 | 5 (3.36) |
| 2003 | 5 (3.36) |
| 2004 | 7 (4.70) |
| 2005 | 9 (6.04) |
| 2006 | 6 (4.03) |
| 2007 | 9 (6.04) |
| 2008 | 13 (8.72) |
| 2009 | 20 (13.42) |
| 2010 | 17 (11.41) |
| 2011 | 16 (10.74) |
| 2012 | 20 (13.42) |
| 2013 | 11 (7.38) |
| 2014 | 4 (2,68) |
| Type of surgery | |
| Conventional | 63 (42.3) |
| Mononuclear cells | 86 (57.7) |
| Bacterial contamination | |
| Gram-aerobic bacilli | 53 (35.6) |
| Non-contamination/mixed flora | 37 (24.8) |
| Aerobic Gram + bacilli | 3 (2.0) |
| Anaerobic Gram + cocci | 2 (1.3) |
| Osteomyelitis | |
| Yes | 56 (37.6) |
| No | 93 (62.4) |
| Type of previous surgery | |
| None | 75 (50) |
| Conventional | 48 (32) |
| Mononuclear cells | 12 (8) |
| Both of them | 15 (10) |
| Comorbidities | |
| Without interest | 61 (40.9) |
| Diabetes mellitus (DM) | 11 (7.4) |
| Cardiovascular diseases | 14 (9.4) |
| Respiratory diseases | 4 (2.7) |
| Renal diseases | 1 (0.7) |
| Anemia | 2 (1.3) |
| Mental disorders | 6 (4.0) |
| Inflammatory bowel disease | 5 (3.4) |
| Liver diseases | 18 (12.1) |
| DM. Cardiovascular diseases | 14 (9.4) |
| DM. Anemia | 7 (4.7) |
| Multi-systemic pathologies | 6 (4.0) |
| Complications | |
| No | 105 (70.7) |
| Failure | 5 (3.3) |
| Dehiscence | 30 (20) |
| Bleeding | 7 (4.7) |
| Hematoma | 2 (1.3) |
To select suitable patients, a series of well-defined inclusion and exclusion criteria were established. The inclusion criteria were as follows: (1) Grade III/IV PIs which would be suitable for direct closure after debridement, (2) age between 18 and 80 years, (3) PIs which had not healed after local treatment for at least 4 months, and (4) signature of the informed consent. The exclusion criteria were as follows: (1) Patients younger than 18 or older than 80 years, (2) contraindication for or insufficient bone marrow aspirate, (3) mental illness, (4) diagnosis or history of malignant cancer, (5) serious concomitant diseases (severe hemorrhagic disorders, hemophilia, severe disseminated intravascular coagulopathy, skin infections, recent radiation therapy, and multiple myeloma if sternal bone marrow aspiration is needed instead of iliac crest), (6) intolerance to the prone position, and (7) patients without spinal cord injury.
One hundred and forty-nine patients were registered with a mean age of 52.29 ± 12.35 years (mean ± standard error). Ninety of the 149 patients between age 50 and 80 were studied. Below 50 years, we find the remaining 59. If we analyze the sample with 20-year ranges, we obtain the following finding: there is one patient between 10 and 29 years old, 58 patients between 30 and 49 years old, 89 between 50 and 79 years old, and one patient aged 80 or more. A total of 128 men (85.91%) and 21 women (14.1%) and a mean hospital stay of 64.09 ± 36.05 days, were obtained. Among all spinal cord injured patients analyzed, 120 were paraplegic (80.5%), while 29 were tetraplegic (19.5%) and, the most common injuries were ischial PIs (104 patients; 69.8%), followed by sacral (26 patients, 17.4%), and trochanteric (19 patients, 12.8%). Regarding laterality, 43.6% were on the right side (65 cases), 39% (58 cases) on the left side, and 17.4% were in the midline (26 cases). Attending to the treatment group, 63 cases (42.3%) suffered conventional surgery, while 86 patients (57.7%) were treated with mononuclear cells obtained from the bone marrow.
Analyzing how many patients were operated each year, the ones with the highest number of registered patients were 2009 and 2012, with 20 cases (13.42% each). However, the year 2000 showed the lowest frequency (2 patients; 1.3%). Regarding bacterial contamination, Gram-aerobic bacilli (53 cases, 35.6%) and non-contamination/mixed flora (37 cases, 24.8%) showed the highest frequency. On the other hand, aerobic Gram + bacilli (3 cases, 2.0%) and anaerobic Gram + cocci (2 cases, 1.3%) were the most uncommon.
The presence or absence of osteomyelitis on MRI images was also studied and it was found that 62.4% (93 patients) did not have osteomyelitis, while 37.6% (56 patients) had. Comorbidities without interest (61 patients; 40.9%) and liver diseases (18 patients; 12.1%) represented the 2 groups with the highest frequencies. On the contrary, kidney diseases (1 patient; 0.7%) were the least frequent among these patients.
Treatment protocol
-
1.
Preoperative studies
Routine preoperative tests were requested. MRI imaging of the pelvic area or fistulous tract to establish its size accurately and determine the presence or absence of osteomyelitis was obtained in all cases. Additionally, bacteriological cultures of the pressure injuries or fistula were taken.
-
2.
Preparing the patient for surgery
The day before surgery a urinary catheterization, antibiotic prophylaxis (Amoxicillin Clavulanic 1 g/8 h, and adjusted intravenous antibiotherapy based on previous cultures all of them under the recommendation of the Infectious Diseases Service), and intestinal cleansing enema were performed.
-
3.
Obtaining mononuclear cells from the bone marrow
Three hours before the surgery, bone marrow aspiration was performed at the posterior superior iliac crest, obtaining about 50–60 cc of autologous cellular material. Afterward, aspirate was diluted in the normal saline in a 1:1 ratio (B. Braun, Melsungen, Germany). Subsequently, the mononuclear fraction was achieved by means of a density gradient with Ficoll (Biocoll separating solution, 1.077 g/ml, Biochrom AG, Berlin, Germany), isolating only the intermediate phase. To remove Ficoll remains and supernatant from mononuclear cells, two washes were carried out in the RPMI-1640 medium (Roswel Park Memorial Institute, Mediatech, VA, USA) and then cells were suspended in the heparinized (20 UI/ml) saline solution (Viaflo sodium chloride 0.9%, Baxter International Inc., Deerfield, IL, USA) until a final volume of 14 ml was obtained. Eventually, 10 ml of this cell suspension was introduced in a sterile syringe and transferred to the operating room. The remaining 4 ml was used for cell counts sterility tests.
-
4.
Procedures performed in the operating room
Surgical intervention began with a debridement of PIs until healthy tissues were found (Fig. 2). Later, in the control group a direct closure of the defect was performed with a non-absorbable suture, while in the cell therapy group, after the closure of the defect, 10 ml of solution containing mononuclear cells was infused or infiltrated within it (Fig. 3).
-
5.
Postoperative care
Figure 2.
Debridement of an ischial pressure injury.
Figure 3.
Infusion of mononuclear cells.
To guarantee the success of surgery, the following are included: (1) elbow and knee protection, (2) daily dressings of the injury, (3) prone position during three weeks, (4) beginning with postural changes throughout the fourth postoperative week to later begin with sitting during the fifth or sixth week. (5) Antibiotherapy was adjusted to cultures until stitches were removed.
-
6.
Postoperative evaluation and follow-up
Photographs of the injury were taken on the first day after surgery, also after the removal of stitches and the day the patient was discharged from the hospital. Subsequently, outpatient follow-up was performed at three months, six months, and one year after surgical intervention.
Statistical analysis
The statistical analysis was carried out using the R program (R Development Core Team), 3.4.4 version. Relationships between qualitative variables were assessed using Pearson’s Chi-square test or Fisher’s test. Differences in quantitative variables between two groups were compared with Student’s t-test for independent samples. All P values were based on two-sided statistical analyses, and for all analyses a P value less than 0.05 was considered to be statistically significant.
Ethical considerations
This study has been carried out in compliance with the ethical and legal recommendations, according to the current regulations that concern Spain and Europe, in compliance with the provisions of regulation (EU) 2016/679 of the European Parliament and organic law 3/2018, of December 5th, protection of personal data and guarantee of digital rights (BOE-A-2018-16673). The data of patients included in the study have been used confidentially.
The study was carried out after obtaining authorization from the Research Ethics Committee of the Principality of Asturias.
Results
Descriptive study
As shown in Fig. 4, within the 4 groups established to study immediate postoperative complications, the one that presented the highest number of registered cases was the dehiscence of the surgical wound, with 19.5% of patients (29 cases), followed by the appearance of hematomas, with 8,7% (13 cases). The least frequent group was the infection of surgical wound (3 patients; 2%).
Figure 4.
Immediate postoperative complications.
At last, results were checked one month, 3, 6 months, and a year after the surgery. It was found that, after a month, 62.4% of the patients (93 patients in total) did not present any type of complication, while 37.6% (56 patients) suffered a dehiscence of the surgical wound. At 3-month post-intervention, it was observed that 99 patients (66.4%) attended with wounds completely closed, while the other 50 (33.6%) presented wound dehiscence or fistula. Later, at 6 months, 76.5% (114 patients) achieved complete wound healing without complications, while only 23.5% (35 patients) developed dehiscence or fistula. Finally, one year after the intervention, it was found that most of them (113 patients; 75.8%) remained free of recurrence, while 24.2% (36 patients) showed signs of recurrence. An example of the postoperative results can be seen in Fig. 5.
Figure 5.
Example of the postoperative results after infiltration-infusion of mononuclear cells from bone marrow.
These photos show the case of a male with a right ischial pressure injury. After surgical debridement, a larger cavity is obtained, which is closed directly by planes. The third photo shows the infiltration-infusion of mononuclear cells from bone marrow after the closure of the wound. We did check-ups at 3, 6 months, and 1 year after surgery. In this case, the patient evolved without complications after cell therapy and, as it can be seen in the last photo taken at 6 months post-operatively, the wound was completely closed.
Comparative study
A comparative study between the two main groups of our sample was carried out, comparing all variables collected.
Relationship between having received conventional treatment or cell therapy and sex (P = 0.312) of patients, age (P = 0.159), etiology of PIs (P = 0.172), location (P = 0.482), and laterality (P = 0.671) of them were analyzed without finding significant differences between any of these characteristics. Similarly, osteomyelitis (P = 0.816), number of previous interventions (P = 0.447), comorbidities including diabetes (P = 0.064), and immediate postoperative complications (P = 0.395) were compared and also no significant differences were discovered.
The association between different types of bacterial contamination and treatment groups was also studied. We found that there was a statistically significant relationship between the type of bacterial contamination and the intervention group (P = 0.008).
Specifically, in patients treated with the conventional surgery, we found 36.51% of cultures without contamination or mixed flora and 28.57% with Gram - aerobic bacilli, while in those treated with cell therapy, 40.70% of patients had cultures with Gram - aerobic bacilli and 27.91%, Gram + aerobic cocci.
When comparing the results regarding the follow-up of the patients enrolled in our study (Figs. 6–9), it was found that at 1 and 3 months after surgery, there were no statistically significant differences (P = 0.566, P = 0.315, respectively) between the conventional surgery and cell therapy. In the end, statistically significant differences were established when we analyzed results at 6 months and one year after the surgery. Therefore, at 6 months, no patient in the conventional surgery group presented dehiscence or fistulization of the wound, while there were 35 (41%) cases with such complications in the group treated with cell therapy (P < 0.001). In addition, one year after the treatment, among those treated with the conventional surgery, only 3.17% recurred, while 39.53% patients relapse in the cell therapy group (P < 0.001).
Figure 6.
Comparison of the results after one month. (Light: no complication. Dark: dehiscence).
Figure 7.
Comparison of the results after 3 months. (Light: no complication. Dark: dehiscence).
Figure 8.
Comparison of the results after 6 months. (Light: no complication. Dark: dehiscence).
Figure 9.
Relapse after a year. (Light: no relapse. Dark: relapse).
Finally, the association between the type of treatment and mean hospital stay was studied, verifying a significant greater number of days of hospitalization in patients treated with the conventional surgery, with a P value of 0.037.
Discussion
As far as we know, there are no studies that show the benefits of the cell therapy with mononuclear cells derived from the bone marrow with the conventional surgery in patients with spinal cord injuries. For that reason, we conducted a study to ascertain the outcome of both treatment approaches.
We work in a new third-level hospital and we have the Cell Therapy and Regenerative Medicine Unit, belonging to the Hematology Service, which is in charge of obtaining these mononuclear cells. This infrastructure is necessary to develop therapies like the one we have exposed here. Although the results of twenty-two spinal cord injured patients treated with mononuclear cells were presented previously and a study about wound healing was published reviewing 30 spinal cord injured patients treated with cell therapy, the whole population that received this treatment in our hospital had not been studied. In addition, results of therapy with mononuclear cells had not been compared before with the conventional surgery.
In our series, we verified that the distribution of patients according to sex and age was similar to that reported by others, such as Jordan et al.14 with 85.1% of men and with a mean age of 41.3 ± 13.8 years. Also regarding the etiology, similarly that was observed in our study, paraplegia is more frequently found than tetraplegia,15,16 and also almost in all studies, the most frequently found PIs are sacral16 and ischial.6 Also the bacterial contamination of PIs in patients with spinal cord injuries, published results are similar to ours, with positive cultures for Gram - aerobic bacilli and for Gram + aerobic cocci being more frequent.17 Regarding osteomyelitis, the proportion of positive cases ranged from 93.2%18 to 16.44%,19 probably in relation to the degree of selected pressure injuries, characteristics of patients, and number of recurrences.
Despite adequate treatment, recurrence rates in PIs are high. In various studies, as in our series, rates of recurrence after surgical intervention ranged from 20% to 25%.20,21 In the study carried out by Morel et al.22 the time of appearance of the recurrences was after 9 months and 52.3% of them required secondary surgeries. Regarding complications, their rates vary among studies. Thus, Lefèvre et al.,21 reported 59.8% of complications, while Ljung et al.23 only found 6%. In our study, 30.2% of patients showed complications after the treatment and the most frequent of them was the dehiscence of surgical wound, as was stated in the Ljung et al.23 study. Here, the mean hospital stay was 64.09 ± 36.05 days, what agrees with data collected in other studies, with mean stays of about 80.5 days.20 Looking at the rates of cure and recurrence, they vary a lot from one study to another, probably due to patients with very different characteristics and various types of treatments followed, and conditions of injuries. There are studies that describe 96% of patients cured one year after surgery,23 something that was never reached in our study at any time. This may be because, in most of studies, treatments of PIs grade III–IV were based on myocutaneous flaps after desbridement.20–23 Coverage with flaps can lengthen hospital stay; however, they offer a more stable coverage with higher rates of healing over time.
In the present study, both groups of treatment were homogeneous in terms of demographic and clinico-pathologial variables and, consequently, initially comparable. Thus, the observed differences are probably due to the treatment, i.e., it was found that there were no statistically significant differences regarding sex and age of patients, and in etiology, location, and laterality of PIs treated with the conventional surgery or cell therapy. Furthermore, various comorbidities inherent to the patients were considered because of their possible relationship with any treatment group. It was established that there was no association between them and the outcome, including diabetes. Additionally, no significant differences were found in concomitant osteomyelitis and in the number of previous interventions. There was no minimum or maximum size after debridement that was used as an inclusion criterion. The only condition was that all the fistulas and the pressure injuries, after debridement and bursectomy, allowed us to directly close without tension and without using grafts or flaps. Our purpose was to compare this new technique of infiltration-infusion of mononuclear cells from bone marrow with the conventional surgery. To make both groups homogeneous, only injuries suitable for the primary closure and without tension were considered and that is the reason why we have excluded those cases that required reconstructive surgery.
Once it was assumed that both treatment groups were comparable, complications in the immediate postoperative period were studied and it was found that neither group had complications more frequently than the other. Many studies have suspected better healing results and fewer complications12,24,25 in spinal cord injured patients who received cell therapy. However, there are no previous studies with a control group to really determine if fewer complications occur with cell therapy than with the conventional surgery. Although no statistically significant differences were established in outcomes at 1 and 3 months, significant differences were identified between both groups in the long-term follow-up, specifically at 6 months and one year after the treatment. It was shown that during the first months after the treatment, results of conventional surgery and cell therapy were considered similar with no significant differences between them. On the other hand, it was after 6 months when the balance leans toward the conventional therapy. This may be due to the contribution of cells derived from bone marrow in early stages of wound healing23 and, taking into account our data, perhaps not in the long term. For the same reason, hospital stay, which would correspond to the first postoperative months, may be significantly shorter in the group treated with cells derived from bone marrow. Mononuclear cells derived from bone marrow constitute a heterogeneous group that includes from mature B cells, T cells, monocytes, and a small percentage of progenitor cells (hematopoietic, mesenchymal, endothelial, and embryonic stem cells).26 The use of mononuclear stem cells has been described in the treatment of chronic wounds and other pathologies.10,11 Recently, a systematic review of 43 articles, published in July 2020,27 highlights that the different types of stem cells can promote healing by restoring the signaling pathways of growth factors, cytokines, and chemokines. This can induce an increase in vascularization and local innervation and modulating inflammatory processes. Bone marrow-derived mononuclear cells simultaneously accelerate the rate of wound healing and decrease wound area compared to the nonstem cell therapy treatment.28 However, there are a few studies that address the duration of the effects of this therapy and, those that were available, only provide data about the presence of these cells between 7 and 14 days after their injection.29,30
Finally, here we found a statistically significant relationship between different classes of bacterial contamination and the type of intervention. In the conventional surgery group, most frequent results of cultures were without contamination or mixed flora and Gram - aerobic bacilli. In contrast, the cell therapy group showed more frequent cultures with aerobic Gram - bacilli and aerobic Gram + cocci. This positive relationship, which implies greater bacterial contamination in the group in which cell therapy was used, perhaps could explain the worse long-term results in this group of patients.
The possibility of studying the effects of infiltration-infusion of mononuclear cells from bone marrow in combination with the benefit of using flaps in the long term could reveal different results; but for now, it must be taken into account that, in the first six months after surgery, results are similar with the two techniques studied but, after that period, conventional surgery is better. It should not be forgotten that the advantage of cell therapy is that it is less aggressive than the conventional or reconstructive surgery.
Conclusion
Based on our results, we can conclude that the use of mononuclear cells derived from bone marrow after surgical debridement does not provide benefits in PIs healing compared to the conventional surgical treatment in the short medium term. It is possible that they can accelerate the healing process contributing to faster recovery, which results in a shorter hospital stay. However, in the long-term analysis, its positive effect seems to disappear, giving to the conventional surgery group a better evolution between 6 months and a year after surgery.
Disclaimer statements
Contributors None.
Funding None.
Conflicts of interest Authors have no conflict of interests to declare.
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