How can we optimize the development of drugs for wound healing?

Vågesjö, Evelina; Grigoleit, P.; Fasth, Andreas E. R.; Phillipson, Mia

doi:10.1080/17460441.2022.1992381

Cited by 4 publications

(4 citation statements)

References 17 publications

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“…Non-healing skin wounds, acute and chronic, are a burden for individual patients and healthcare systems. Vågesjö and colleagues outlined present therapeutic modalities, their limitations ( 26 ) and the need for more and better studies. With the discovery of specific growth factors and cytokines, the hope increased to use these in therapeutic settings to improve the granulation of wounds, infiltration of leukocytes for host defense, and wound closure.…”

Section: Discussionmentioning

confidence: 99%

Physiological fibrin hydrogel modulates immune cells and molecules and accelerates mouse skin wound healing

et al. 2023

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IntroductionWound healing is a complex process to restore homeostasis after injury and insufficient skin wound healing is a considerable problem in medicine. Whereas many attempts of regenerative medicine have been made for wound healing with growth factors and cell therapies, simple pharmacological and immunological studies are lagging behind. We investigated how fibrin hydrogels modulate immune cells and molecules in skin wound healing in mice.MethodsPhysiological fibrin hydrogels (3.5 mg/mL fibrinogen) were generated, biophysically analyzed for stiffness and protein contents and were structurally studied by scanning electron microscopy. Physiological fibrin hydrogels were applied to full thickness skin wounds and, after 3 days, cells and molecules in wound tissues were analyzed. Leukocytes, endothelial cells, fibroblasts and keratinocytes were explored with the use of Flow Cytometry, whereas cytokines and matrix metalloproteinases were analyzed with the use of qPCR, ELISAs and zymography. Skin wound healing was analyzed microscopically at day 3, macroscopically followed daily during repair in mice and compared with commercially available fibrin sealant Tisseel.ResultsExogenous fibrin at physiological concentrations decreased neutrophil and increased non-classical Ly6Clow monocyte and resolutive macrophage (CD206+ and CX3CR1+) populations, at day 3 after injury. Fibrin hydrogel reduced the expression of pro-inflammatory cytokines and increased IL-10 levels. In line with these findings, gelatinase B/MMP-9 was decreased, whereas gelatinase A/MMP-2 levels remained unaltered. Frequencies of dermal endothelial cells, fibroblasts and keratinocytes were increased and keratinocyte migration was enhanced by fibrin hydrogel. Importantly, physiological fibrin accelerated the healing of skin wounds in contrast to the highly concentrated fibrin sealant Tisseel, which delayed wound repair and possessed a higher fiber density.ConclusionCollectively, we show that adding a tailored fibrin hydrogel scaffold to a wound bed positively influences the healing process, modulating leukocyte populations and inflammatory responses towards a faster wound repair.

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Section: Discussionmentioning

confidence: 99%

Physiological fibrin hydrogel modulates immune cells and molecules and accelerates mouse skin wound healing

et al. 2023

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“…Tolerability, clinical and biologic effects were assessed at each visit (SAD: Day 1, 2, 3, 7, 14, and at 6 weeks, 3 months and 12 months from start of treatment at Day 1; MAD: Day 1,2,3,5,8,10,12,15,17,19,21,32, and at 6 weeks, 3 months and 12 months after last dose at Day 19). All assessments were blinded and occurred by on-site visual inspections of the wounds by the Principal Investigator (or co-investigator), as well as off-site by traceable evaluation and detailed wound area measurements from 2D photographs of all wounds by 3 Independent Evaluators (IEs) with expertise in wound healing.…”

Section: Discussionmentioning

confidence: 99%

Live Biotherapeutics : importance of formulation and lyophilization parametersand an example of a clinical application

Tyagi

2023

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In recent years, probiotics have expanded from their traditional classification as “health promoting food” to the development of live biotherapeutic products (LBP). Traditional probiotics are marketed as food/dietary supplements while LBPs are drug products intended for treatment or prevention of diseases. This type of products offers several advantages over traditional drugs, but also entail potential challenges with development, manufacturing, and demonstration of clinical safety. To obtain a sufficient quality, LBPs are typically produced by cultivation in a bioreactor, followed by formulation and lyophilization. In the first part of the project, the impact of lyophilization parameters on physicochemical and biological properties of Limosilactobacillus reuteri R2LC was evaluated. Using sucrose as a lyoprotectant gave a better freeze-drying survival, vitality and storage stability than using trehalose. A high concentration (20%) of sucrose sometimes resulted in a collapsed structure and 15% gave the overall best properties of the lyophilized bacteria. Interestingly, vitality was positively affected by using a higher concentration (1010 cfu/ml) of bacteria. Another observation was that introducing an annealing step in the process was positive when using sucrose as lyoprotectant, but no effect was seen when using trehalose. The second part of the project describes evaluation of the genetically modified L. reuteri R2LC expressing the human chemokine CXCL12 (ILP100-Topical) in a phase 1 trial on wound healing. The product was safe and well-tolerated. In addition, it gave a larger proportion of healed wounds (76 %) on Day 32 when compared to saline/placebo (59 %) (p=0.020) and the time of wound healing was reduced by 6 days on average and by 10 days at highest dose. Also, ILP100-Topical increased the density of CXCL12+ cells in the wounds and local wound blood perfusion.

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“… 23 , 24 In 2020, the FDA identified five new primary endpoints for consideration: PAR over 4 weeks, reduced infection, reduced pain, increased ambulation, and quality of life. 25 Of these, PAR is the only truly quantitative metric, and so offers the best opportunity for statistical power in study design.…”

Section: Discussionmentioning

confidence: 99%

A Novel Randomized Trial Protocol for Evaluating Wound Healing Interventions

Bull

Clements

Collarte

et al. 2023

Advances in Wound Care

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Background: Randomized controlled trials using complete healing as an endpoint suffer from poor statistical power, owing to the heterogeneity of wounds and their healing trajectories. The Food and Drug Administration (FDA) has recently consulted with expert groups to consider percentage area reduction (PAR) of the wound over a 4-week period as a valid intermediate endpoint, creating the opportunity for more powerful study designs. Methods: A within-subject controlled study design comparing the PAR of venous leg ulcers (VLU) in patients over 4 weeks receiving different interventions. Twenty-nine patients received multilayer compression over 4 weeks, followed by neuromuscular electrostimulation (NMES) of the leg muscle pump in addition to compression for a further 4 weeks. Paired comparison was then made of PAR between the two phases. A second cohort of 22 patients received only multilayer compression throughout both 4-week phases. Results: Patients randomized to NMES saw a significant increase in healing rate compared with compression alone, whereas patients receiving compression only saw no significant change in healing rate throughout the course of the study. Conclusions: Intermittent NMES of the common peroneal nerve significantly accelerates the healing of VLU. It is well tolerated by patients and deserves serious consideration as an adjuvant to compression therapy. PAR is a useful metric for comparing the performance of wound healing interventions, and the self-controlled trial design allows sensitive discrimination with a relatively small number of subjects over a reasonably short trial period. The study is reported according to the CONSORT reporting guidelines. Clinical Trial Registration: NCT03396731 (ClinicalTrials.gov).

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How can we optimize the development of drugs for wound healing?

Cited by 4 publications

References 17 publications

Physiological fibrin hydrogel modulates immune cells and molecules and accelerates mouse skin wound healing

Physiological fibrin hydrogel modulates immune cells and molecules and accelerates mouse skin wound healing

Live Biotherapeutics : importance of formulation and lyophilization parametersand an example of a clinical application

A Novel Randomized Trial Protocol for Evaluating Wound Healing Interventions

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