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Advanced Healthcare MaterialsBioengineeringPeer-reviewed journal article

Mechanically Compliant, Precision-Porous Brain Implants Reduce the Foreign Body Reaction and Guide Regeneration

Ian D. DrygiD, Le ZheniD, Rebecca Darrow, Savannah LawtoniD, Lars Crawford, Robert Robinson, Steve I. PerlmutteriD, James D. BryersiD, Buddy D. RatneriD

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Abstract

Central nervous system diseases and injuries might be treated by implanted devices, tissue regenerative scaffolds, or drug delivery platforms. However, inflammatory CNS responses limit these interventions and may worsen outcomes following damage to the CNS. Via the foreign body reaction, macrophages and glial cells trigger a "glial scar" around implants, reducing device performance, scaffold regenerative ability, or drug delivery potential. Previous studies have shown that stiffness of CNS implants significantly affects glial encapsulation, but few studies have investigated materials that truly match brain tissue stiffness. Porous precision-templated scaffolds with uniform, interconnected, 40 {micro}m spherical pores have shown favorable healing outcomes and a reduced FBR in numerous soft and hard tissue applications. To quantify the effects of both hydrogel compliance (stiffness) and pore size on glial encapsulation, we implanted poly(2-hydroxyethyl methacrylate-co-glycerol methacrylate) (pHEMA/GMA) scaffolds of varying stiffness and pore size for 4 weeks in rat brain. We observed reduced astrocyte encapsulation around PTS compared to solid hydrogel rods, reduced pro-inflammatory macrophage polarization for softer hydrogels versus stiffer hydrogels, and the presence of new blood vessels, neuronal markers and neurogenesis within the pores. Utilizing soft, precision-porous hydrogels could provide a strategy for mitigating glial scarring and improving regeneration in implant-based CNS treatments.

In-depth summary

Claude Opus 5.5 · xhigh effort · 8 Nov 2026 · from the full text of version 4 (29 Jul 2026) · CC BY 4.0

Brain-stiffness-matched pHEMA/GMA hydrogel scaffolds with 40 µm interconnected pores reduced astrocyte encapsulation and iNOS+ macrophage fraction versus stiff solid rods after 4 weeks in rat brain.

Foreign body reactions driven by macrophages and glia encapsulate CNS electrodes, scaffolds and drug depots, yet many implant stiffness studies used materials orders of magnitude stiffer than brain. The authors report the first brain test of precision-templated porous scaffolds, whose 30-40 µm pores minimize fibrosis in other tissues, and combine this architecture with hydrogel compliance matched to brain.

Key results

  1. ShownPairing brain-like compliance with 40 µm pores reduced astrocyte (GFAP) encapsulation compared with stiff, nonporous rods. Stiffness, porosity and their interaction were all significant factors.

    GFAP fluorescence 0-25 μm from the implant edge, n=8 rats, two-way ANOVA: stiffness p=9.46E-6, porosity p=4.44E-6, interaction p=2.86E-5. Tukey vs 50% water nonporous: 85% water 40 μm pores p=0.0152; 75% water 40 μm pores p=0.0136. · Soft, porous implants reduce astrocyte…; Tissue Processing and Histological Analysis; Statistical Analysis

  2. ShownThe softest 40 µm porous scaffolds lowered the share of pro-inflammatory (iNOS+) cells among peri-implant CD68+ cells compared with stiff solid implants. The pro-healing Arg1+ share did not change.

    iNOS+ % of CD68+ within 100 μm: two-way ANOVA stiffness p=6.78E-3, interaction p=3.63E-2, porosity not significant. Tukey 85% water 40 μm pores vs 50% water nonporous p=0.0395. Arg1+ % of CD68+: no significant effects. · Compliant, porous implants improve…; Tissue Processing and Histological Analysis

  3. ShownSeveral readouts did not respond to stiffness or pore size: microglial (iba1) encapsulation, macrophage counts, Arg1 polarization and peri-implant neuron density. In the 50% water group, leaving out gelatin reinforcement produced no differences in tissue response.

    iba1 within 25 μm: no significant effects (trend paralleled GFAP). NeuN+ density within 50 μm: no significant two-way ANOVA effects. Gelatin-free 50% water group: no differences from its gelatin+ counterpart. All materials had endotoxin <0.025 EU/ml (sterile standard <0.06 EU/ml). · Results; Soft, porous implants reduce astrocyte…; Porous implants promote integration of neural…

  4. SuggestedHost tissue grew into the porous scaffolds. Endothelial (RECA1) labeling showed vessels running through the pores, and axonal, dendritic and neuronal nuclear markers appeared inside the pore network.

    Confocal immunofluorescence (representative images): Neurofilament, MAP2 and NeuN+ cells seen within PTS pores; RECA1 staining throughout the porous structure. No vessel density or in-pore neuron counts were reported. · Porous implants promote integration of neural…; 40 µm PTS promote angiogenesis and neurogenesis; Figure legends

  5. SuggestedCells positive for both NeuN and doublecortin appeared only inside 40 µm pores. The authors read this as possible neurogenesis within the scaffold but say it needs careful interpretation.

    In follow-up staining, NeuN+ DCX+ cells were seen within 40 µm PTS pores but not in surrounding tissue, at analyzed depths of 1-1.5 mm (likely neocortex). No BrdU, Nestin or Ki-67 labeling was performed; candidate sources (SVZ migration, astrocyte or OPC conversion) were not tested. · 40 µm PTS promote angiogenesis and neurogenesis; Discussion

Methods, data and reproducibility

pHEMA/GMA (1:1) hydrogels made with 50%, 75%, or 85% pre-polymer water were cast as solid films or PMMA bead-templated with 40 or 100 µm pores, punched into rods, lyophilized, gelatin-reinforced, and implanted 1cm deep in rat brain for 4 weeks; outcomes were quantified by immunofluorescence (radial GFAP/iba1 profiles, band-based cell counts) and two-way ANOVA.

  • Young adult female Sprague-Dawley rats, each receiving all twelve hydrogel rod implants (six per hemisphere, randomized); nine gelatin-reinforced groups quantified at 4 weeks · rat (Sprague-Dawley) · n = 8 rats (n=8 biological replicates)
  • Horizontal 50 µm vibratome brain slices at 1-1.5 mm implant depth, immunostained; control regions >1 mm from any implant in the same slice · rat
  • pHEMA/GMA hydrogel disks (5mm diameter, 1mm thick) tested for compressive Young's modulus in hydrated and lyophilized states · n = N=3 hydrated; N=1 lyophilized
  • Leftover porous film segments from implant punching, assayed for endotoxin
Methods & tools
PMMA microbead sphere-templating for porous templated scaffold (PTS) fabrication, Scanning electron microscopy, Instron 5543 compression testing with Bluehill 2 software, 0.83% agar gel brain-insertion test, Zeiss LSM 510 confocal microscope, FIJI (ImageJ) custom scripts with Radial Profile Angle plugin and Cell Counter, statsmodels (two-way ANOVA, Tukey HSD), Statannotations with Matplotlib and Seaborn, IF markers: GFAP, iba1, CD68, iNOS, Arg1, NeuN, MAP2, Neurofilament, Doublecortin, RECA1, Pierce Chromogenic Endotoxin Quant Kit (Thermo Scientific)
Reagents & environment
Python statsmodels (ols, anova_lm, pairwise_tukeyhsd), Statannotations with Matplotlib and Seaborn; FIJI (ImageJ) custom scripts with Radial Profile Angle plugin; Instron Bluehill 2. No other software versions reported.
Reproducibility gaps
No code or data availability statement. The custom FIJI analysis scripts are not linked, no image data are deposited, hydrogel recipes appear only in Figure 1b, and stiffness values (Table S1) and antibody details (Table S2) are in supplementary material not included in the text.
Limitations (6)
  • The 85% water implants could not penetrate the agar brain-mimic even when lyophilized, so implants in all water content groups were given a double gelatin reinforcement before insertion. · stated by the authors
  • Lyophilized high-water solid films showed micro-porosity (<30 μm at 75% water, <50 μm at 85% water). Whether these pores exist when the material is hydrated is unknown. · stated by the authors
  • The neurogenesis reading is tentative: the adult neocortex rarely supports neurogenesis, the proposed mechanisms were not tested, and BrdU, Nestin and Ki-67 labeling are left for future work. · stated by the authors
  • Tissue was examined at a single time point (1 month). The authors note the low M1 levels inside pores could reflect this timing as an alternative to accelerated healing. · stated by the authors
  • Each rat (n=8) carried twelve implants, but the ordinary two-way ANOVA treated them as independent, with no animal random effect. Neighboring implants in a hemisphere could also affect each other, and few Tukey contrasts reached significance. · noted in this summary
  • There were no functional readouts (impedance, recordings, behavior) and in-pore vessels and neurons were not quantified. The lyophilized modulus rests on N=1, so benefits at the device level are inferred, not shown. · noted in this summary

Read this if you develop soft or porous neural interfaces, CNS regenerative scaffolds, or brain drug depots and want rat histology on how hydrogel stiffness and pore size shape glial scarring and macrophage polarization.

Citations
1
FWCI
2.19
Field percentile
top 11%

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