diabetic foot ulcer: a meta-analysis efficiency of stem cell based … · 2018. 7. 16. · patients...

©The Japan Endocrine Society

Original

Efficiency of stem cell based therapy in the treatment ofdiabetic foot ulcer: a meta-analysisXuan Shu1), Shenyou Shu1), Shijie Tang1), Lvjun Yang2), Dan Liu1), Ke Li1), Zejun Dong1), Zhongchao Ma3),Zhensen Zhu1) and Jialong Din1)

1) Department of Burn and Plastic Surgery, 2nd Affiliated Hospital of Shantou University Medical College, Shantou 515041, China2) Translational Medicine Center, 2nd Affiliated Hospital of Shantou University Medical College, Shantou 515041, China3) Department of Orthopaedics, Jinxiang Hospital Affiliated to Jining Medical College, Shandong 272200, China

Abstract. Diabetic foot ulcer is a chronic, refractory, frequent complication in diabetic patient. Its treatment often requiresmultidisciplinary joint efforts, diverse strategies have been adopted to address this annoying issue, including stem cell-basedtherapy/acellular dermal matrix/negative pressure wound therapy etc. However, consensus has not been reached. To assess thecurrent evidence regarding the efficiency and potential advantages of stem cell-based therapy compared with conventionalstandard treatment and/or placebo in the treatment of diabetic foot ulcer. A comprehensive search in PubMed, EmBase,Cochrane Central and Web of Science databases was conducted during December 2016 and a systematic review and meta-analysis of all relevant studies were performed. A total of 7 studies that involved 224 diabetic foot patients, classified asWagner grades 1–5, were analyzed. The pooled results confirmed the benefits of using the stem cell treatment. Partial and/orcomplete healing were significantly higher in the stem cell group compared with the control group (77.4% vs. 31.9%; RR:2.22; 95% CI, 1.65–2.98). Subgroup analysis on ABI and TCP02 also confirmed the results. The present meta-analysisindicates that stem cell-based therapy can enhance the healing of diabetic foot ulcers and is associated with lesser pain, loweramputation rate and improved prognosis compared with normal treatment. Well-designed randomized controlled trials arerequired in the future in order to confirm and update these findings.

Key words: Diabetic foot ulcer, Stem cell-based therapy, Wound healing, Meta-analysis

doi:10.1507/endocrj.EJ17-0424

DIABETES MELLITUS (DM) comprises a group ofcommon metabolic diseases which results in commonsocial and economic burden. According to Boulton et al.in 2002, the direct and indirect expenditures that wereattributable to diabetes were estimated to 132 billion dol‐lars [1]. It is believed that the number of diabetic patientsworldwide will rise to 430 million by 2030 [2]. One ofthe serious chronic complications of DM is the diabeticfoot. Among all diabetic patients, approximately 20% to25% will develop foot problems in their lifetime. Thesesymptoms are usually accompanied by a majority ofcomplications, such as chronic pain at rest, lower

Submitted Oct. 19, 2017; Accepted Dec. 20, 2017 as EJ17-0424Released online in J-STAGE as advance publication Jan. 22, 2018Correspondence to: Shenyou Shu, Department of Burn and PlasticSurgery, 2nd Affiliated Hospital of Shantou University MedicalCollege, No. 69, Dongxia North Road, Jinping District, 515041,China.E-mail: [email protected]

extremity weakness, intermittent claudication, ulcer,recurrence of ulcer, and/or even amputation in some rarecases [3]. The cause of diabetic foot ulcer is multifacto‐rial and neuropathy and/or peripheral vascular abnormal‐ities are considered as the main etiological factors [4].

Currently, the standard care for treating diabetic footulcer includes offloading, control of foot infection, con‐trol of ischemia, wound debridement, and wound dress‐ing [5]. However, diabetic foot ulcers require a long timeperiod for successful healing, and the majority of thepatients fail to heal, resulting in foot ulcer, gangrene andlimb amputation [6]. Thus, an effective method to accel‐erate the healing of diabetic foot ulcer is required. Stemcell-based therapy has been considered as a novel treat‐ment for diabetic foot disease both in animal models andhuman experimentation [7-9].

As a branch of regenerative medicine, stem cell ther‐apy is the use of stem cells to repair and even replacedamaged tissues or organs based on ex vivo/in vivo stim‐

Endocrine Journal Advance Publication Endocrine Journal Advance Publication

ulation of stem cell expansion and differentiation intofunctional progeny [10]. Stem cells can be indentifiedand separated from many kinds of tissues such as adi‐pose, bone marrow, embryonic, peripheral blood, umbili‐cal cord and so on [11]. But only when the kind of stemis massive, easy to obtained, induced in a controllablemanner, safety and effectively, that they be applied inclinical care. The application of embryonic stem cellswas restrained due to ethical consideration, whileinduced pluripotent stem cells (iPSCs) are limited duefor safety and effectively uncertainties [12]. At present,the most common used stem cells are bone marrowderived stem cells and adipose derived stem cells. Since1968 the first successful bone marrow transplantationstem cell based therapies have existed. Over the 50 yearsit has been all along considered as the future of medicine[13]. However even numerous basic experiments havefocus on the subject but unfortunately only a little of thencome in to clinical practice, and even lesser became astandard clinical care. Several clinical trials [14-16] haveevaluated the efficacy of stem cell treatment, althoughthese trials were conducted on small sample sizes. There‐fore, a systematic review was conducted in order to eval‐uate the effectiveness of stem cell-based therapy in thetreatment of diabetic foot ulcers.

Methods

Eligibility criteriaStudies were eligible if they adhered to the following

criteria: (1) Publication in English language, (2) Inclu‐sion of human subjects, (3) Involvement of clinical trialsand originality of the study, (4) Report of outcomes (5)Comparison of stem cell therapy with placebo and/orconventional treatment. (6) The incidence of diabeticfoot ulcers in the subjects. The participants who werecandidates for either other stem cell treatments and/orendovascular revascularization studies were excluded.All participants included should not show evidence ofimprovement in response to standard therapy four weeksand/or longer prior to the initiation of the study. Studieson animals, reviews, case reports and non-original stud‐ies were excluded. There was no age restriction.

Information sources and search strategyA thorough search of the PubMed, EmBase, Cochrane

CENTRAL and Web of Science databases was conduc‐ted for related studies. The first search was conducted onthe 11th of December 2016 and the final search was on

the 20th of December 2016. Controlled vocabulary (e.g.medical subject headings terms) supplemented with key‐words was used to define the concepts of stem cell ther‐apy and diabetic foot ulcers. The following search termswere used: 1) diabetic foot ulcers, diabetic foot ulcer,diabetic foot, diabetic ulcer, DFU; paired with 2) stemcell, stem cell therapy, progenitor cell, bone marrowstem cells, cell treatment, stem cell transplantation. Norestrictions were imposed. A manual search for the refer‐ences of the original and review articles was conductedfor additional, possibly relevant studies.

Study selectionFollowing removal of the duplicate studies, two of the

authors working independently screened the titles andabstracts for eligibility according to the pre-definedinclusion criteria. Disagreements were automaticallyupgraded to the next level of screening. Based on thetitle and/or abstracts, full texts of articles that potentiallymet the inclusion criteria were obtained and carefullyscreened in duplicate. Disagreements at this level wereresolved by consensus and/or discussion with the thirdauthor.

Data collectionA total of two authors independently extracted and

collected specific information for each study that wasincluded according to the inclusion criteria selected. Theinformation was as follows: name of the author, coun‐tries of the studies, year of publication, study design,characteristics of the included patients, Number of par‐ticipants, type and duration of diabetes, data of ulcers,interventions received, follow-up duration, healing rate,baseline of transcutaneous arterial oxygen tension(TcPO2), ankle brachial index (ABI) and incidences ofadverse events. The discrepancies between the twoauthors were then resolved by a second review of full-text, a thorough discussion and a finalized consensus.Additional information was requested from the studyauthor for studies that presented results by charts and/orgraphs. In case of a poor response provided by theauthor, the Dig XY software (version 1.2) was used inorder to measure the graphs and obtain the data. How‐ever, the accuracy of such data may be considered poorand susceptible to bias.

Statistical analysisA total of two reviewers independently assessed the

quality of the included studies. The assessment of the

2 Shu et al.


study quality is summarized in Fig. 1. We used the ‘Riskof bias’ tool as described in the “Cochrane Handbook forSystematic Reviews of Interventions” in order to com‐plete the evaluations. The domain assessment includedcriteria concerning aspects of assessment allocation,sequence generation, blinding, incomplete outcome data,selective reporting and potential threats to the validity ofthe study. The primary outcome for evaluating efficacywas a partial and/or complete healing rate. The change inABI and TcPO2 was further analyzed as representativeparameters of revascularization, since both were nonin‐vasive and easily reproducible [17]. The Risk ratios(RRs) with 95% confidence intervals (CIs) were appliedfor the analyses of dichotomous data, whereas continu‐ous data were presented as the standardized mean differ‐ence with 95% CIs. A random-effects model was used toestimate the merged result in order to minimize the influ‐ence of potential heterogeneity [18]. I2 analysis was con‐

Fig. 1 Risk of bias summary: the authors’ judgements with regardto each risk of bias item for each included study.

ducted in order to test for heterogeneity among studies.An I2 of higher than 50% (I2 > 50%) was considered toindicate statistically significant heterogeneity [19]. Allstatistical analyses were conducted using Review Man‐ager Software (Rev Man) [Computer program]. (Version5.3. Copenhagen: The Nordic Cochrane Centre, theCochrane Collaboration, 2014).

Results

Study selectionA total of 406 studies were identified by the initial

search. Following careful screening of titles andabstracts, 399 articles were excluded leaving 7 articlesthat fulfilled the predefined inclusion criteria and wereincluded in the final analysis [20-26]. A total of 6 publi‐cations were full-text articles out the 7 studies [20,22-26], whereas 1 publication was a meeting conference[21]. The detailed inclusion and exclusion criteria areshown in Fig. 2.

Characteristics of eligible studiesThe basic characteristics of the 7 included studies are

presented in Tables 1, 2. These studies were publishedbetween 2009 and 2016. A total of 2 studies were con‐ducted in China, whereas the remaining 5 were conduc‐ted in Iran, Egypt, Germany, Czechoslovakia and India,respectively. It is important to note that 3 studies (Lu2011, Karina 2012, Dubsky 2013) reported 2 differenttypes of stem cell interventions. Accordingly, 2 compari‐sons were derived. According to the Cochrane hand‐book’s recommendation, the same size control group wasequally distributed to the 2 types of interventional groupsin order to overcome a unit of analysis error. A total of224 diabetic foot patients with or without ulcers wereincluded, of which 122 were included in the experimen‐tal group and 102 in the control group. A total of 59patients out of the 122 in the experimental group weretreated with mesenchymal stem cells (3 bone marrow-derived and 1 granulocyte colony stimulating factor (G-CSF)-mobilized umbilical cord-derived), 40 were treatedwith bone marrow-derived mononuclear cells, 11 weretreated with peripheral blood progenitor cells and 12were treated with marrow-enriched tissue repair cells.The mean patient age in the included studies ranged from30 to 78, and partial and/or complete healing rangedfrom 29% to 86%. The follow-up duration period variedfrom 12 to 45 weeks.

Stem cells for diabetic foot ulcer 3


Adverse eventsA total of 4 out of the 7 included studies reported

adverse events, such as death, leg edema, sudden strokeor major amputation [23-26]. However, no evidence indi‐cated that these adverse events were stem cell therapy-related. In the Dubsky’s study, one transient elevation ofCRP in the bone marrow mononuclear cell-group wasobserved [25]. The most common adverse event wasmajor amputation and it was noted at a higher incidencein the control group compared with the stem cell group.The incidence of the remaining adverse events exhibitedno significant difference between the stem cell and con‐trol groups. The detailed information is summarized inTable 3.

Quality assessmentThe risk of bias of the included studies was evaluated

by the Cochrane assessment tool (Figs. 2, 3). The overallquality of the included studies was moderate, with thequality of the included studies ranging from low to mod‐erate. A total of 6 of the included studies were random‐ized controlled studies, with the exception of 1 study(Dubsky 2013) that was not randomized due to the ethi‐cal considerations.

A total of 3 studies adequately reported the detailedmethods of sequence generation, and one study describedallocation concealment. A total of 6 studies reportedwithdrawal and dropout details, whereas 2 studies mayhad potential bias of selective outcome, and some were

Fig. 2 Flow diagram for studies identified, included, and excluded.

4 Shu et al.


uncertain due to the lack of a protocol publication thatdescribed their performance. A total of 5 studies reportedpartial and/or complete healing rate in both the stem celland control groups, whereas 2 studies reported ABI andTcPO2 changes as a healing indicator. Additional poten‐tial sources of bias were not identified based on thepresent assessment. No baseline imbalance was men‐tioned in the studies examined.

Effect of stem cells on diabetic foot ulcer healingThe pooled data from 5 studies that assessed healing

rate in 150 patients indicated that partial and/or completehealing were significantly higher in the stem cell groupcompared with the control group (77.4% vs. 31.9%; RR:2.22; 95% CI, 1.65–2.98) (Fig. 4). No significant hetero‐geneity was detected. A total of 3 comparisons, involv‐ing 47 patients evaluated the effects of stem cells on themean size of the ulcer. A random-effects model indicatedthat stem cell-based therapy may enhance ulcer sizereduction compared with the control group. Among the 3studies investigated, the mean difference ranged from–2.98 cm2 to –8.06 cm2, with a combined mean differ‐ence of –3.48 cm2 (95% CI, –4.62 – –2.33) (Fig. 5). Atotal of 3 studies reported that the change noted in ABIin 106 patients, as demonstrated by the ABI index, wassignificantly higher in the stem cell group (mean differ‐ence, 0.17; 95% CI, 0.12–0.22, p < 0.0001) (Fig. 6). Bycontrast, the 3 aforementioned studies reported that thechange of TcPO2 in 135 patients was accompanied witha heterogeneity that was noted following the pooling of

the studies (x2 = 85.09; DF = 4, p < 0.001; I2 = 95%)(Fig. 7). The pooled studies indicated a significant differ‐ence that was in favor of the stem cell group (MD, 17.11mmHg, 95% CI, 5.96–28.27).

Sensitivity analysis and publication biasA total of 7 studies were included in the sensitivity

analysis. No significant change was noted with regard tothe outcomes investigated, with the exception of thedegree of heterogeneity in the TcPO2 group that wasdecreased following the removal of the study by Qin etal. [20]. The funnel plot was not used to assess publica‐tion bias as it was deemed inappropriate, as recommen‐ded by the Cochrane handbook due to the small numberof studies included [27].

Discussion

Wound healing is a complex and dynamic process.Following skin injury, the mutual interaction between thecells and extracellular matrix (ECM) is an important fac‐tor in the process of healing. The soluble factors contrib‐ute to injury healing. This process involves certain keyevents, such as angiogenesis, neovascularization and therelease of growth factors [28, 29] that are impaired indiabetic patients. An acute wound develops into a non-healing ulcer in diabetic foot patients, due to the dam‐aged peripheral microvasculature and nerves. Thissymptom is further associated with several complicationsnamely, chronic resting pain, lower extremity weakness,

Table 1 Summary of study characteristics

Author, year Country Study design Cell type Amount of cells Placebo Method Follow up

Dash, 2009 India Rct Bmmscs 106/cm2 None i.m. 12w

Lu, 2011 China Rct Bmmscs Unclear n.s. i.m. 6w

Bmmncs Unclear n.s. i.m. 6w

Kirana, 2012 Germany Rct Bmmncs >3 × 107 None i.m. or i.a. 45w

Bmtrcs >5 × 107 None i.m. or i.a. 45w

Dubsky, 2013 Czech Cct Bmmnc 53.4 ± 11.4 mL None i.m. 24w

Pbpcs 63.6 ± 19.9 mL None i.m. 24w

Mohammadzadeh, 2013 Iran Rct Autologous Mscs 1.5–2.0 × 107 cells per site Sterile PBS i.m. 12w

Qin, 2016 China Rct Humscs 4.8 × 107 None i.m. 12w

Albehairy, 2016 Egypt Rct Mscs 3.7 × 105 per cm2 None i.m. 12w

Abbreviations: Bmmscs, human bone marrow-derived mesenchymal stem cells; Bmmncs, bonemarrow mononuclear cells; Bmtrcs, bone marrowtissue repair cells; Pbpcs, peripheral blood progenitor cells; Mscs, mesenchymal stem cells; Humscs, human umbilical cord mesenchymal stemcells; PBS, phosphate-buffered saline; n.s., normal saline; i.m., intramuscular injection; i.a., intra-arterial injection; RCT, random controlled trial;CCT, controlled clinical trial; w, weeks.



Tabl

e 2

Basic

cha

ract

erist

ics o

f pat

ient

s in

the

incl

uded

stud

ies

Aut

hor,

year

Gro

up/

subg

roup

Num

ber o

fPa

tient

sM

ean

Age

(yea

rs, m

ean

SD)

Mal

e%

DM

type

DM

dur

atio

n(y

ears

)

TcPO

2ba

sline

(mm

Hg)

Ulc

erBa

selin

e(c

m2 )

ABI

Pain

-free

wal

king

dista

nce

Rest

pain

Hea

ling

perc

enta

ge(%

)

Das

h, 2

009

Bmm

scs

340

± 1

01

or 2

——

7.26

± 1

.41

——

——

Cont

rol

340

± 1

01

or 2

——

4.24

± 0

.76

——

——

Lu, 2

011

Bmm

scs

1163

± 8

391

or 2

10.3

± 5

.642

.7 +

10.

14.

2 ±

2.9

0.55

± 0

.10

1.1

± 0.

43.

4 ±

0.6

Bmm

ncs

1165

± 1

042

1 or

29.

8 ±

5.0

44.5

+ 1

0.5

4.3

± 3.

10.

53 ±

0.1

01.

2 ±

0.4

3.5

± 0.

5

Cont

rol

2168

1 or

243

.5 +

10.

04.

5 ±

2.3

0.54

± 0

.09

1.1

± 0.

43.

5 ±

0.5

Kira

na, 2

012

Bmm

ncs

1268

.5 ±

1.5

751

or 2

20.9

± 4

.3—

9.6

± 4.

2—

——

83

Bmtrc

s12

70.9

± 1

.783

1 or

220

.5 ±

3.9

—7.

7 ±

2.7

——

—80

Dub

sky,

201

3Bm

mnc

1760

.7 ±

9.4

88.2

223

.1 ±

15.

216

.3 ±

11

5.2

± 1.

6—

——

Pbpc

1163

.4 ±

10.

481

.82

21.5

± 9

.416

.4 ±

9.8

5.5

± 1.

7—

——

Cont

rol

2263

.3 ±

9.1

77.3

219

.8 ±

914

.6 ±

9.6

5.9

± 2

——

—

Moh

amm

‑Adz

adeh

, 201

3A

utol

ogou

sM

SCs

763

.5 ±

7.8

—2

16.5

+ 8

.714

.2 ±

4.1

——

—86

Cont

rol

1464

.2 ±

7.8

—2

14.2

± 8

.515

.8 ±

17.

0—

——

29

Qin

, 201

6H

UCM

SCs

2875

± 3

60.7

212

.8 ±

7.2

24 ±

3—

3 ±

1.5

——

78.9

Cont

rol

2573

± 5

602

13.1

± 4

.622

.5 ±

6—

2.85

± 4

.5—

——

Alb

ehai

ry, 2

016

Msc

s10

—50

216

.40

± 5.

314.

66 ±

2.2

2

Cont

rol

10—

702

13.3

0 ±

6.36

3.72

± 1

.87

Abb

revi

atio

ns: A

BI, a

nkle

bra

chia

l ind

ex; T

cPO

2, tr

ansc

utan

eous

oxy

gen

pres

sure

.

6 Shu et al.


Table 3 Summary of adverse events

Author, year Group Number ofpatients

Adverse eventsOthers

Infection Major amputation Death

Dubsky, 2013 Bmmncs 17 1 2 1 (cardiac failure) 4 leg edema

Pbpcs 12 0 1 0 3 leg edema 1 temporary pain

Control 22 0 10 2 (1 severearterial bleeding1 cardiac failure) Unclear

Karina, 2012 Bmmncs 12 0 2 1 1 stroke

Bmtrcs 12 0 0 1 Unclear

Control 6 0 1 2 Unclear

Dash, 2009 Bmmscs 3 0 0 0 Unclear


Lu, 2011 Bmmsc 11 0 0 2 Unclear

Bmmnc 11 0 0 2 Unclear


Fig. 3 Risk of bias graph: The authors’ judgements with regard to each risk of bias item were presented as percentages across all includedstudies.

Fig. 4 Forest plot and meta-analysis depicting risk ratios of complete and/or partial healing of diabetic foot ulcer for stem cell therapygroup and control groups; M-H = Mantel-Haenszel method; CI = confidence interval. (Vertical line represents the point of nodifference between the stem cell therapy group and control group. Squares = risk ratios; diamonds = pooled risk ratios for allstudies. Horizontal lines = 95% CIs).



intermittent claudication, infection, recurrence, ulcera‐tion and major amputation. Conventional standard treat‐ment, such as debridement and control of glucose,always take a long while to repair wound or failed torepair, or even wore lead to wound deterioration such asinfection, local necrosis or amputation. A previousreview showed with good standard wound care, in 12weeks only 24 percentages wound healed [30]. StandardDFU treatment to some extent keep a moist wound topromise tissue regeneration, but it cannot repair the dam‐aged microcirculatory system and/or the impaired releaseof growth factors [31]. Stem cells are known for theirmulti-potent ability to differentiate and for their exten‐sive self-renewal. These features could overcome theaforementioned complications [32]. Several meta-analyses have shown that stem cell therapy may improvecritical limb ischemia, although the analysis of the effect

of stem cell therapy on diabetic patients has not beeninvestigated to date. Thus, the present study was conduc‐ted in order to analyze the association between stem cell-based therapies and improved healing with reduction inthe size of diabetic foot ulcers.

This meta-analysis comprised 7 studies, involving 224diabetic foot patients and aimed to compare the efficacyof stem cell-based therapy and conventional treatment.The results indicate that stem cell therapy is a moreeffective therapeutic strategy. Stem cell therapy canaccelerate the healing of chronic skin ulcers in the dia‐betic foot patients and it can improve the microvascularregeneration around the wound area. In addition, as sta‐ted in the GCP guidelines for the conduct of clinical tri‐als, the safety and well-being of the trial subjects and/orthe patients are the most important considerations andshould prevail over interest of science and society. The

Fig. 5 Forest plot and meta-analysis of mean difference between the stem cell therapy and the control groups, change of ulcer size area(cm2). CI, confidence interval; SD, standard difference.

Fig. 6 Forest plot and meta-analysis of the mean difference of the change in ABI between the stem cell therapy and the control groups.CI, confidence interval; SD, standard difference.

Fig. 7 Forest plot and meta-analysis of mean difference of change in TcPO2 between the stem cell therapy and the control groups, CI,confidence interval; SD, standard difference.

8 Shu et al.


significant difference of the amputation rate between thestem cell and the conventional groups indicates that thisnovel treatment strategy provides greater safety. It isimportant to note that the prior- and -after treatmentchanges of the two commonly used prognosticindicators- ABI and TcPO2- were also significantly dif‐ferent between these two groups, suggesting that thisprocedure may have improved long-term effects. A totalof 6 types of stem cells were included in the presentanalysis. The results that were derived from the studyconducted by Dubsky et al. indicated that the bone mar‐row was a preferable source compared with the periph‐eral blood for the isolation of stem cells. Despite thisadvantage, peripheral blood progenitor cells are isolatedmore readily compared with bone marrow mononuclearcells. A subgroup analysis of different stem cells wasattempted, although this type of analysis was restrictedby the small number of studies. Since 1968 the first suc‐cessful bone marrow transplantation stem cell basedtherapies have existed. Over 50 years numerous basicexperiments had emerged. But only a little of then cameinto clinical care. In our analysis, we only obtainedresearches form restricted areas. There may be some rea‐sons prevent form stem cells’ bench to besides. First, theclinical use of stem cell derived stem cell derived prod‐ucts are varies substantially between countries. Forexample in USA, Canada and EU the clinical trial aretightly regulated. In USA, to perform a clinical trial ofhuman cell based therapies, permission from FDA isneeded. The FDA considered autologous stem cells simi‐larly to allogeneic stem cells, both of them are requiredmultiple pre-clinical test of safety and efficacy [33]. Thedetailed regulation is in Title 21, part 1271 of the Codeof Federal Regulations (C.F.R.). Second, the amounts ofobtained stem cell form participants before the treatmentare usually small. To enrich cell concentration, cell cul‐ture, passage and induced differentiation in vitro are nec‐essary. That requires a relatively high-level laboratorytechnique which may restrain the application of suchresearches in some undeveloped areas. Besides, somestem cell may lose function or mutate due to impropriateinduced process or too many passages. That’s a potentialthreaten to the safety and efficacy of the treatment [12].Third, religions such as Catholic and some Christiangroups are object to stem cell use. Especially allogenicstem cells and embryonic stem cells, they believe thatsuch produce offends the sanctity of life (Catholic doc‐trine 162). Considered nearly 25 percent of Americansbelieve the Catholic, the religion belief may be a poten‐

tial barrier in the clinical research. Fourth, as the techni‐que of stem cell therapy rapidly developing, severalethnic issues been raised too, that’s also the main reasonhinder the application the application of embryonic stemcells. For other kind of MSCs, the main challenges washow to minimization the harm, how to face over expecta‐tions, how to solve therapeutic misconception and so on[34]. To all, the clinical use of stem cells is limited notonly because of the issues of safety and efficacy, thepolitical, legal, religion, socioeconomic and ethical fac‐tors should also take into consideration. The moving for‐ward of stem cell therapy is the blench of creativity andcaution, even make controversies exists, the developmentof it is essential and will benefit both science andpatients in the future.

Although our analysis indicates the benefits of autolo‐gous stem cell-based therapy for diabetic foot ulcers, itcannot be confirmed that the optimized procedure is fullyfunctional due to lack of data. Hence, larger sample sizesand thorough clinical studies are required in order todetermine whether the source, the dose and/or the deliv‐ery method of stem cells are critical factors for the suc‐cessful conduct of the procedure.

The limitations of the present meta-analysis areaswere as follows: 1) the small number of studies included,which limits the analysis of publication bias; 2) theincluded studies did not distinguish diabetic foot fromcritical limb ischemia. Although all the patients includedexhibited varying characteristics of foot pathologiesnamely, ulceration, neuropathic osteoarthropathy andperipheral arterial disease, the etiology and pathophysiol‐ogy of the ulcers caused by critical limb ischemia andDM were different; 3) The criteria of healing were differ‐ent among the 7 studies, with 5 of 7 using complete heal‐ing rate and the remaining 2 using ulcer size reduction asthe measurement of healing. Some of the key data weremissing, which did not allow us to analyze the woundhealing baseline; 4) certain studies were poorly designed.Although the authors referred to their studies as randomcontrolled trials, the random sequences were not men‐tioned and/or clearly described. In one study, not all par‐ticipants experienced ulcers, whereas the number ofpatients with ulcers was not clarified. This could causebias in the analysis. An additional potential limitationwas that the failure to report the patient’s foot care prac‐tice and data by the studies investigated. Despite theexposed therapy, proper foot self-care agents, such asoff-loading shoes and antimicrobial agents, can reducethe risk of ulcers and enhance wound closure [35, 36].



Conclusion

The currently available evidence derived from thestudies analyzed confirms that stem cell therapy is apromising novel treatment strategy for diabetic footpatients [37]. It further provides evidence that stem cellsmay be associated with shorter recovery time, rapid tis‐sue regeneration and lower limb amputation. Future stud‐ies should focus on optimizing the procedure for stemcell therapy, such as identifying the optimal dose, and theprimal subgroup of stem cells. Furthermore, a largersample size and well-designed, comprehensive clinicaltrials are required to confirm and update the findings ofthis analysis.

Acknowledgements

The primary author has full control of all primary data,which may be assessed by contacting the correspondingauthor. The author would like to thank the ExecutiveDirector of LKS Shantou University Foundation FriedaLaw for excellent technical support and critically review‐ing the manuscript.

Conflict of Interest

None of the authors have any potential conflicts ofinterest associated with this research.

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