Biology subjects

Drack, A.

Publications and source records attributed to Drack, A..

3 recordsLinked to original sources

bioRxiv2026

Adhesive silk hydrogel patches for localized and sustained delivery of cell-derived nanovesicles

The transplantation of stem cell-derived extracellular vesicles (EVs) holds promise for tissue repair and regeneration, but scalable production and effective delivery to target tissue remain major challenges. Here, we present a biomaterial platform that combines high-yield, scalable nanovesicles (NVs) - EV mimetics derived from human induced pluripotent stem cells - with an adhesive silk hydrogel patch for localized and sustained delivery. We show that this platform enables efficient NV encapsulation via visible light crosslinking and supports controlled release over short (2 days), intermediate (7 days), and extended (up to 28 days) periods, while maintaining adhesion to heart tissue. Importantly, the sustained delivery of NVs for 3 days in vitro results in promoting anti-fibrotic cell remodeling and significant functional recovery of primary myofibroblast activation, modulating integrin signaling, actomyosin organization, and cell-matrix adhesion networks. Finally, we demonstrate biocompatibility, retention, and anti-fibrotic function of the patch in a murine ischemia-reperfusion injury model. Thus, we establish the proof-of-principle that di-tyrosine silk hydrogels can be used as a strategy to encapsulate and deliver NVs to the heart, thus offering an innovative delivery platform for NVs. Statement of significanceExtracellular vesicles (EVs) represent an emerging frontier in tissue engineering. Their cell-specific cargo contains biological information capable of repairing and regenerating injured tissues. However, their clinical translation is hindered by limited manufacturing scalability, undefined dosing and modes of administration, and low organ retention, particularly in the heart. This study addresses these challenges by combining stem cell-derived nanovesicles (NVs), which mimic biological EVs, with an adhesive hydrogel patch for localized and sustained delivery to the heart. We provide proof-of-principle that di-tyrosine photo-crosslinked silk hydrogels are a suitable delivery platform for cell-derived NVs, preserving NV bioactivity and their ability to remodel recipient cells following delivery both in vitro and in vivo. This study integrates three key advantages: (i) the use of scalable iPSC-derived nanovesicles as an EV-mimetic platform, addressing limitations in EV manufacturing; (ii) a mechanically robust and tunable silk fibroin hydrogel formed via visible light-induced di-tyrosine crosslinking without chemical modification; and (iii) an injection-free, adhesive patch-based delivery strategy enabling localized and sustained therapeutic administration to the heart. This innovative platform represents a significant advancement in the fields of nanomedicine and biomedical engineering. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/722555v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@fed253org.highwire.dtl.DTLVardef@1a270b0org.highwire.dtl.DTLVardef@19437c1org.highwire.dtl.DTLVardef@1d863ca_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG

bioengineering↗

bioRxiv2024

Single-cell transcriptional and epigenetic mapping reveals cellular and molecular mechanisms driving non-ischemic cardiac fibrosis

Cardiac fibrosis is a major cause of cardiac dysfunction. Recently, single-cell genomic approaches have revealed in unprecedented resolution the orchestrated cellular responses driving cardiac fibrosis. Yet, the fibrosis-causing phenotypes that emerge in the heart following non-ischemic cardiac stress, and the transcriptional circuits that govern cell identity and drive fibrosis, are not well understood. Applying a paired multiomic approach, we reveal key transcriptional circuits, in mouse and human hearts, which are associated with fibrosis development following non-ischemic cardiac insults, independent of disease model, species or biological sex. Strikingly, we find the key regulatory events driving fibrosis are reversible at the single-cell transcriptional and epigenomic level, further pointing to key factors regulating fibrosis development and resolution. The transcriptional regulators identified in this study represent promising targets to ameliorate the development of fibrosis in the context of chronic stressors such as aging and hypertension.

cell biology↗

bioRxiv2023

An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked Retinoschisis.

IntroductionX-linked retinoschisis (XLRS) is a vitreoretinal dystrophy caused by RS1 gene mutations which disrupt retinoschisin protein function. A vital protein for maintaining retinal architecture, the absence of functional retinoschisin leads to the development of intraretinal cysts. The preliminary goal of this study was to investigate a low dose gene therapy in Rs1 knockout (Rs1-KO) mice; however, our experiments revealed an unexpected therapeutic effect of a hypertonic buffer, which led to further exploration of this effect. Methods10 Rs1-KO mice were subretinally injected with an AAV2/4 vector containing the RS1 gene driven by an Ef1 promoter. 16 Rs1-KO mice were subretinally injected with a hypertonic buffer (180 mM NaCl 0.001% F68/PBS (pH 7.4)) or an isotonic buffer (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) as a sham control. Endpoints included electroretinogram (ERG), optical coherence tomography (OCT), and a visually guided swim assay (VGSA). An immunohistochemistry assay was used to quantify cone density in buffer injected and treatment-naive eyes. ResultsUnexpectedly, hypertonic buffer-injected eyes had significantly reduced cyst severity at 1 month post-injection (MPI) (p=<0.0001), significantly higher amplitudes in cone-dominant ERGs persisting to 5 months post-injection (5 Hz flicker; p=0.0018; 3.0 Flash; p=0.0060) and demonstrated improved navigational vision in the light compared to untreated Rs1-KO eyes (p<0.0001). To investigate the role of tonicity on this effect, an isotonic buffer-injected cohort was created (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) (n=6). Surprisingly, hypertonic buffer-injected eyes exhibited a greater reduction in cyst severity and demonstrated improved cone-dominant ERG metrics over isotonic buffer-injected eyes. Using an immunohistochemistry assay, we demonstrated greater cone density in hypertonic buffer-injected eyes than untreated controls (p=0.0147), suggesting a possible cone preservation mechanism. Moreover, our findings reveal a negative correlation between the peak severity of cysts and long-term cone-dominant ERG metrics, implying that effectively managing cysts could yield enduring benefits for cone function. Discussion/ConclusionThis study presents evidence that cyst resolution can be triggered through an osmosis-dependent pathway, and cyst resolution can have long term effects on cone signaling and survival, offering potential insights for the development of novel treatments for patients with XLRS.

genetics↗